Potential GABAB Receptor Antagonists. X* the Synthesis of Further Analogues of Baclofen, Phaclbfen and Saclofen

Article abstract of DOI:10.1071/C97031

In an attempt to obtain new compounds with binding activity at the GABA_B receptor site, we report the synthesis of 3-amino-2-arylpropanoic acids, and the sulfonic, phosphonic and hydroxamic acid analogues. In addition, we report the synthesis of the isomer of phaclofen, 3-amino-1-(4-chlorophenyl)-propylphosphonic acid, and the higher homologue of baclofen, 5-amino-2-(4-chlorophenyl)pentanoic acid.

Full text of DOI:10.1071/C97031

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 50, 1997
© CSIRO Australia 1997
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Aust. J. Chem., 1997, 50, 813–823
Potential GABA Receptor Antagonists. Xꢀ
B
The Synthesis of Further Analogues of
Baclofen, Phaclofen and Saclofen
Rolf H. Prager and Karl Schafer
Department of Chemistry, Flinders University of South Australia,
G.P.O. Box 2100, Adelaide, S.A. 5001.
In an attempt to obtain new compounds with binding activity at the GABA receptor site, we report
B
the synthesis of 3-amino-2-arylpropanoic acids, and the sulfonic, phosphonic and hydroxamic acid
analogues. In addition, we report the synthesis of the isomer of phaclofen, 3-amino-1-(4-chlorophenyl)-
propylphosphonic acid, and the higher homologue of baclofen, 5-amino-2-(4-chlorophenyl)pentanoic
acid.
Cl
Cl
Introduction
In previous papers,1,2 we have reported the synthe-
sis of a number of shortened chain analogues (2)–(5)
of baclofen (1), in which the amino side chain was
decreased by one carbon atom. Since there was
still signiꢀcant activity in some of these analogues
H2N
CO2H
X
H2N
(2) X = CO2H
as GABA antagonists,3,4 we have synthesized some
(1)
B
(3) X = PO3H2
(4) X = SO3H
(5) X = NO2
analogous compounds, in which the carboxyl side chain
was decreased by one carbon, and an extended chain
analogue of baclofen. The compounds described have
all been synthesized in the racemic form; it is our
intention to devise enantioselective syntheses for only
those compounds with signiꢀcant biological activity.5
hoped that a common intermediate, the bromo phthal-
imide (10), would prove useful. Unfortunately (10)
failed to undergo the required substitution; it was
found to undergo only elimination with cyanide ion to
give the alkene (11) (95%), and failed completely to
react with triethyl phosphite or sodium bisulꢀte.
The synthesis of the required acids was achieved
less directly. Bromination of the relevant ethyl arylac-
etate with N-bromosuccinimide proceeded smoothly
on irradiation in the presence of benzoyl peroxide
to give the bromo esters (12) and (13), as did the
Discussion
3-Amino-2-(4-chlorophenyl)propanoic acid (8) and
3-amino-2-phenylpropanoic acid (9) were prepared in
good yields by hydrolysis/decarboxylation of the phthal-
imides (6) and (7) respectively as shown in Scheme 1.
As the corresponding phosphonic and sulfonic acids
were also required for comparison, it was originally
X
X
X
(i) NaH
HCl
O
O
C
(70%)
C
EtO2C
EtO2C
(ii)
N
CH2Br
N
NH2
CO2Et
C
HO2C
EtO2C
C
O
O
(87%)
X = Cl or H
(6) X = Cl
(7) X = H
(8) X = Cl
(9) X = H
Scheme 1
ꢀ
Part IX, Aust. J. Chem., 1997, 50, 523.
Manuscript received 3 March 1997
0004-9425/97/080813$05.00
10.1071/CH97031

814
R. H. Prager and K. Schafer
O
X
X
X
C
N
CH2Br
C
P(OEt)3
(83%)
O
O
C
EtO2C
(64%)
N
Br
CO2Et
(EtO)2(O)P
CO2R
(EtO)2(O)P
C
X
R
(12) X = Cl
(13) X = H
O
(14) Cl Et
(16) X = Cl
(17) X = H
(15)
(22)
H
H
Et
H
OH–, 20o
(84%)
X
X
HCl
O
H
(81%)
NH2
N
C
(HO)2(O)P
(EtO)2(O)P
HO2C
(18) X = Cl
(19) X = H
(20) X = Cl
(21) X = H
Scheme 2
as it could lead to a possible explanation for the
sharp decrease in biological activity noted between
O
O
the GABA agonist (24) and its inactive analogue, the
B
C
C
N
dialkylated compound (25).7,8 In addition, a number of
hydroxamic acids are known to have a wide spectrum
of biological activity.9–11
N
Br
C
C
O
O
The previously prepared phthalimido esters (6) and
(7) were converted by base hydrolysis and decarboxyl-
(10)
(11)
Arbuzov reaction with triethyl phosphite (Scheme 2).
The corresponding anions of the phosphonoacetates
(14) and (15) were again alkylated with N-bromo-
methylphthalimide to give the esters (16) and (17).
Alkaline hydrolysis of (16) and (17), under conditions
milder than those normally required to hydrolyse a
phthalimide, surprisingly resulted in selective hydrol-
ysis and decarboxylation. The resulting phthalamides
(18) and (19) were then readily hydrolysed to (20)
and (21) under acidic conditions.
X
O
C
(EtO)2(O)P
N
C
EtO
HO
C
O–
O
X = Cl or H
It is suggested that the tetrahedral intermediate
from hydroxide addition to the ester is responsible
for the intramolecular hydrolysis of the phthalimide,
as shown in Scheme 3, but the reason for the fortu-
itous decarboxylation is not known. Indeed, similar
hydrolysis of the phosphinyl ester (15) did not lead to
decarboxylation, the acid (22) being isolated in good
yield.
The amino sulfonic acid (23) was readily available
by adaptation of the work of Heath and coworkers,6
by addition of bisulꢀte to the chloro nitrostyrene,
followed by catalytic reduction. Finally we reasoned
that the hydroxamic acid (30) would also be of interest
X
O
(EtO)2(O)P
H
N
C
EtO
C
(18) or (19)
HO
O
C
O
Scheme 3

Potential GABA Receptor Antagonists. X
815
B
Cl
Cl
Cl
The ready availability of the cyano malonate (32)
prompted us to convert it into the amide analogue (39).
A review of the literature shows that amides have not
been widely tested as GABA receptor substrates: in
principle, similar hydrogen-bonding possibilities exist
as in an amine, but it is unlikely to bear a positive
charge by protonation. The cyano malonate (32) was
hydrolysed and decarboxylated by the use of 3 equiv.
of hydroxide in ethanol, and then the cyano group was
hydrolysed to the amide by treatment with concentrated
sulfuric acid at 20ꢀ.16
NH2
O2N
R
NH2 HOHN
NH2
HO3S
C
O
R
(23)
(24) R = H
(30)
(25) R = Me
ation into the diacids (26) and (27), which served
as precursors of the hydroxamic acids (28) and (29)
as shown in Scheme 4. Attempts to deprotect the
phthalimide from the phthalimido hydroxamic acid
intermediate (28) with 5 M HCl were unsuccessful,
giving the acid (8) instead, but hydrazinolysis allowed
the smooth conversion into (30).
Having now developed some generally successful
strategies to make the above amino acids, we felt it
seemed logical to investigate the synthesis of analogues
with longer carbon chains. We were encouraged by the
work of Yamasaki and Goto,12,13 who showed that 4-
amino-2-(4-chlorophenyl)butanoic acid (36) stimulated
X
X
SOCl2
O
(98%)
O
C
C
H
N
N
Cl
HO2C
C
O
C
O
HO2C
(26) X = Cl
(27) X = H
NH2OH
(54%)
gastric secretion, possibly by activation of a GABA
B
X
receptor. The literature synthesis of this compound
involved four steps with an overall yield of 0ꢀ67%.14
The simple synthesis summarized in Scheme 5, which is
a modiꢀed version of that of Leonard,15 is a considerable
improvement on this synthesis.
The overall yield in the three-step process was 60%,
and this approach was also applied to the dechloro
compound (37). The synthetically equivalent process
to the ꢀrst step of Scheme 1, where the malonate anion
is alkylated with N -bromoethylphthalimide, resulted
only in the alternative elimination pathway to give the
vinylphthalimide (38).
X
NH2NH2
O
C
(62%)
N
HOHN
NH2
HOHN
C
O
C
O
C
O
(28) X = Cl
(29) X = H
(30) X = Cl
(31) X = H
Scheme 4
X
X
X
H2/PtO2
(i) NaH
(ii) BrCH2CN
(82%)
(84%)
EtO2C
CN
EtO2C
EtO2C
NH2
CO2Et
X = Cl or H
EtO2C
EtO2C
(32) X = Cl
(33) X = H
(34) X = Cl
(35) X = H
(i) KOH
(ii) conc. H2SO4
(81%) HCl
X
Cl
CONH2
NH2
HO2C
HO2C
(39)
(36) X = Cl
(37) X = H
Scheme 5

816
R. H. Prager and K. Schafer
The general methodology of Scheme 2 could be applied
Biological Activity
The amino and amido acids were examined as GABA
to the synthesis of 3-amino-1-(4-chlorophenyl)propyl-
phosphonic acid (42) and its dechloro analogue (43).
The former is an isomer of phaclofen,17,18 which has
signiꢀcant activity as a speciꢀc antagonist of GABA and
baclofen. Alkylation of (14) with bromoacetonitrile gave
the cyano ester (40) which was subjected to hydrogena-
tion and acidic hydrolysis/decarboxylation to give (42)
in an eꢁcient overall process. The dechloro analogue
(43) was prepared from (15) in an analogous manner.
B
receptor antagonists/agonists at the guinea pig ileum.20
In cases where activity was observed, the chlorinated
analogue was more active then the dechloro derivative.
The hydroxamic acid (30) was found to be a very
weak non-speciꢀc antagonist in the ileum (pA2 <3ꢀ0).
The amino acid (36), an isomer of baclofen (1), was
found to weakly antagonize the action of baclofen with
a pA2 of 3ꢀ0. The amido acid (49) was observed to
be a very weak agonist (pA2 <3ꢀ0). Compound (8),
a structural analogue of baclofen with a shortened
chain length, and the related phosphonic (20) and
sulfonic acid (23) analogues were all found to be
inactive at a concentration of 5ꢁ10ꢁ4 M. Compounds
(39), (42) and (46) were also found to be inactive at
this concentration. The biological testing results, while
disappointing, highlight the importance of the site of
placement of the aryl group on the GABA backbone.
O
C
N
CH CH2
C
X
X
O
(38)
EtO2C
CN
NH2
(HO)2(O)P
(EtO)2(O)P
(40) X = Cl
(41) X = H
(42) X = Cl
(43) X = H
Experimental
With the synthesis of shortened chain analogues
and isomers of baclofen now completed, it was decided
to investigate the synthesis of higher homologues by
using the intermediates synthesized above. Alkylation
of diethyl 4-chlorophenylmalonate with N -(3-bromo-
propyl)phthalimide proceeded only poorly, but the use
of acrylonitrile as the electrophile19 gave the cyano
diester (44) in 82% yield. Reduction of the nitrile,
followed by acidic hydrolysis and decarboxylation, then
produced the desired amino acids (46) and (47). As
should be anticipated, reduction of (45) required acidic
conditions to prevent the cyclization of the amine to
the lactam, which was isolated in the case of compound
(48). As was the case with the synthesis of the amido
acid (39), the higher homologue (49) was eꢁciently
obtained from the cyano diester (44) by ꢀrst reacting
it with base and then with sulfuric acid (73% overall).
General
Melting points were determined on a Reichert hot-stage
microscope and are uncorrected. 1H and 13C n.m.r. spectra
were recorded at 300 and 75 MHz respectively from CDCl3
solutions unless otherwise stated, with tetramethylsilane as
internal standard, on a Varian Gemini (300 MHz) spectro-
meter. In samples where D2O was employed as the solvent,
acetone (2ꢀ1 ppm for 1H and 29ꢀ8 ppm for 13C) was used as
the internal reference. Infrared spectra were recorded on a
Perkin–Elmer 1600 Fourier-transform spectrometer; solids were
measured as Nujol mulls and liquids as ꢀlms unless otherwise
stated. Mass spectra were recorded on a Kratos MS25-RF
spectrometer. Column chromatography was performed on
Merck Kieselgel 60 (230–400 mesh ATSM). Drying and other
puriꢀcation of organic solvents were carried out by standard
laboratory procedures.21 Microanalyses were determined by
Chemical and Micro Analytical Services, Melbourne.
Diethyl (4-Chlorophenyl)(phthalimidomethyl)propanedioate (6)
X
X
Diethyl
(4-chlorophenyl)propanedioate22
(3ꢀ10 g, 11ꢀ5
mmol) was added dropwise to a stirring suspension of sodium
hydride (0ꢀ50 g of a 60% dispersion in mineral oil, 12ꢀ5 mmol) in
tetrahydrofuran (40 ml), at room temperature under nitrogen.
A solution of N -bromomethylphthalimide23 (3ꢀ0 g, 12ꢀ5 mmol)
in tetrahydrofuran (20 ml) was added dropwise and the mixture
was stirred overnight. The reaction mixture was quenched with
saturated aqueous ammonium chloride solution (20 ml) and the
solvent evaporated under vacuum. The residue was extracted
with ether (3ꢁ40 ml) and the combined extracts were washed
sequentially with water and saturated sodium chloride solution,
dried, ꢀltered and evaporated under reduced pressure. The
residue was recrystallized from light petroleum/ether to give the
ester (6) as white crystals (4ꢀ28 g, 87%), m.p. 103–105ꢁ (Found:
C, 61ꢀ9; H, 4ꢀ7; N, 3ꢀ6%; M+ꢂ, 429ꢀ0969. C22H20ClNO6
requires C, 61ꢀ5; H, 4ꢀ7; N, 3ꢀ3%; M+ꢂ, 429ꢀ0979). ꢀmax
1778, 1716, 1348, 1258, 1224, 1192, 1094, 1032, 990, 918, 854,
EtO2C
EtO2C
NH2
CN
HO2C
(44) X = Cl
(45) X = H
(46) X = Cl
(47) X = H
Cl
CO2Et
O
720 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ30, t, J 7ꢀ2 Hz, 6H; 4ꢀ28–4ꢀ39, m,
NH
HO2C
CONH2
4H; 4ꢀ58, s, 2H; 7ꢀ19, d, J 8ꢀ8 Hz, 2H; 7ꢀ42, d, J 8ꢀ8 Hz, 2H;
7ꢀ66–7ꢀ77, m, 4H. 13C n.m.r. ꢁ 13ꢀ87; 43ꢀ75; 61ꢀ13; 62ꢀ33;
(48)
(49)

Potential GABA Receptor Antagonists. X
817
B
123ꢀ75; 128ꢀ22; 129ꢀ84; 131ꢀ57; 132ꢀ90; 134ꢀ11; 134ꢀ37;
167ꢀ56; 168ꢀ68. Mass spectrum m/z 431/429 (M, 1/2%),
385/383 (1/2), 226/224 (14/42), 160 (100), 147 (31), 104 (38).
s, 1H; 7ꢀ34–7ꢀ45, m, 4H. Mass spectrum m/z 277/275 (M,
2/1%), 199/197 (16/41), 154/152 (18/54), 141/139 (19/15),
127/125 (33/100).
Diethyl Phenyl(phthalimidomethyl)propanedioate (7)
Ethyl Bromophenylacetate (13)
Diethyl phenylpropanedioate (2ꢀ74 g, 11ꢀ6 mmol) was
treated in the same manner as above. The title compound (7)
was recrystallized from light petroleum/ether as white crystals
(3ꢀ70 g, 81%), m.p. 74–76ꢁ (Found: C, 66ꢀ8; H, 5ꢀ3; N, 3ꢀ6%;
M+ꢂ, 395ꢀ1392. C22H21NO6 requires C, 66ꢀ8; H, 5ꢀ4; N,
3ꢀ5%; M+ꢂ, 395ꢀ1369). ꢀmax 1776, 1732, 1428, 1392, 1344,
Ethyl phenylacetate (10ꢀ0 g, 61 mmol) was brominated
as above.
Kugelrohr distillation aꢂorded the title com-
pound (13) (9ꢀ5 g, 75%) as a colourless oil, b.p. 98ꢁ/1ꢀ0 mm
(lit.26 143–145ꢁ/10ꢀ0 mm) (Found: M+ꢂ, 241ꢀ9983. Calc. for
C
10H11BrO2: M+ꢂ, 241ꢀ9943). ꢀmax 2981, 1743, 1496, 1455,
1369, 1304, 1279, 1215, 1144, 1024, 869 cmꢃ1
.
1H n.m.r. ꢁ
1327, 1258, 1174, 1100, 1029, 991, 794 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ30,
1ꢀ26, t, J 7ꢀ2 Hz, 3H; 4ꢀ23, q, J 7ꢀ1 Hz, 2H; 5ꢀ34, s, 1H;
7ꢀ35–7ꢀ44, m, 5H. Mass spectrum m/z 242 (M, 9%), 169 (84),
163 (85), 141 (27), 135 (48), 107 (49), 91 (100), 79 (79), 51 (76).
t, J 7ꢀ1 Hz, 6H; 4ꢀ27–4ꢀ41, m, 4H; 4ꢀ60, s, 2H; 7ꢀ21–7ꢀ46, m,
5H; 7ꢀ64–7ꢀ73, m, 4H. 13C n.m.r. ꢁ 13ꢀ89, CH3; 43ꢀ98, CH2;
61ꢀ69, C; 62ꢀ16, CH2; 123ꢀ29; 127ꢀ90; 128ꢀ07; 128ꢀ35; 131ꢀ68;
133ꢀ97; 134ꢀ41; 167ꢀ57, CO; 168ꢀ95, CO. Mass spectrum m/z
395 (M, 16%), 349 (41), 303 (15), 276 (23), 248 (23), 190 (100),
160 (84), 147 (44), 104 (70), 76 (64).
Ethyl (4-Chlorophenyl)diethoxyphosphinylacetate (14)
A
mixture of ethyl bromo(4-chlorophenyl)acetate (12)
(10ꢀ0 g, 36ꢀ1 mmol) and freshly distilled triethyl phosphite
(7ꢀ80 g, 47ꢀ0 mmol) was reꢁuxed under an atmosphere of
nitrogen for 5 h. Kugelrohr distillation of the reaction mixture
gave the title compound (14) (10ꢀ02 g, 83%) as a colourless
Hydrochloride Salt of 3-Amino-2-(4-chlorophenyl)propanoic
Acid (8)
The ester (6) (0ꢀ40 g, 0ꢀ93 mmol) was reꢁuxed in 8 M
hydrochloric acid (30 ml) for 12 h. The aqueous solution
was washed with dichloromethane, and evaporated to dryness
under reduced pressure. The crude solid was recrystallized
from ethanol/ether to aꢂord the acid (8) (0ꢀ15 g, 70%) as
its hydrochloride, m.p. 184–187ꢁ (dec.) (Found: C, 46ꢀ0; H,
4ꢀ6; N, 6ꢀ2%; M+ꢂ ꢂ (HCl+NH3), 182ꢀ0129. C9H11Cl2NO2
requires C, 45ꢀ8; H, 4ꢀ7; N, 5ꢀ9%; C9H7ClO2 requires m/z,
182ꢀ0129). ꢀmax 3137, 2639, 2527, 1715, 1583, 1495, 1206,
oil, b.p. 120–122ꢁ/0ꢀ5 mm (Found: C, 49ꢀ8; H, 5ꢀ8%; M+ꢂ
,
,
334ꢀ0747.
C
14H20ClO5P requires C, 50ꢀ2; H, 6ꢀ0%; M+ꢂ
334ꢀ0736). ꢀmax 2984, 2937, 1737, 1492, 1445, 1392, 1368,
1258, 1149, 1092, 973 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ21, t, J 7ꢀ1 Hz,
3H, POCH2CH3; 1ꢀ24, t, J 7ꢀ1 Hz, 3H, POCH2CH3; 1ꢀ27, t,
J 7ꢀ1 Hz, 3H; 3ꢀ99–4ꢀ10, m, 4H, P(OCH2CH3)2; 4ꢀ12–4ꢀ21,
m, 2H; 4ꢀ28, d, JH–P 23ꢀ6 Hz, 1H; 7ꢀ31, d, J 8ꢀ0 Hz, 2H; 7ꢀ48,
d, J 8ꢀ0 Hz, 2H. 13C n.m.r. ꢁ 13ꢀ96; 16ꢀ20, d, JC–P 5ꢀ7 Hz,
POCH2CH3; 16ꢀ26, d, JC–P 5ꢀ5 Hz, POCH2CH3; 51ꢀ48, d,
JC–P 134ꢀ1 Hz; 61ꢀ85; 63ꢀ11, d, JC–P 7ꢀ2 Hz; 63ꢀ38, d,
JC–P 6ꢀ7 Hz; 128ꢀ57, d, JC–P 3ꢀ6 Hz; 129ꢀ62, d, JC–P 8ꢀ7 Hz;
130ꢀ98, d, JC–P 6ꢀ5 Hz; 133ꢀ93, d, JC–P 2ꢀ5 Hz; 167ꢀ16. Mass
spectrum m/z 336/334 (M, 2/5%), 200/198 (20/57), 154/152
(15/42), 127/125 (88/100), 89 (33).
1187, 1096, 1014, 978 cmꢃ1
.
1H n.m.r. (D2O) ꢁ 3ꢀ39, dd,
J 7ꢀ3, 13ꢀ2 Hz, 1H; 3ꢀ63, dd, J 7ꢀ8, 13ꢀ2 Hz, 1H; 4ꢀ11,
apparent t, J 7ꢀ4 Hz, 1H; 7ꢀ34–7ꢀ47, m, 4H. 13C n.m.r. (D2O)
ꢁ 41ꢀ19; 48ꢀ23; 129ꢀ60; 129ꢀ96; 133ꢀ25; 134ꢀ20; 174ꢀ65. Mass
spectrum m/z 184/182 (M ꢂ (HCl+NH3), 22/63%), 165/163
(15/29), 154/152 (17/36), 140/138 (35/57), 139/137 (98/100),
127/125 (62/21), 113/111 (14/30), 103/101 (28/41), 91/89
(19/32).
Ethyl Diethoxyphosphinylphenylacetate (15)
The title compound (15) was prepared as above from (13)
(10ꢀ4 g, 42ꢀ8 mmol) and triethyl phosphite (9ꢀ2 g, 56ꢀ0 mmol).
Kugelrohr distillation gave the ester (15) (10ꢀ4 g, 81%) as a
colourless oil, b.p. 110–112ꢁ/0ꢀ2 mm (lit.26 180ꢁ/3ꢀ0 mm)
Hydrochloride Salt of 3-Amino-2-phenylpropanoic Acid (9)
This compound was prepared from (7) as described above.
Recrystallization of the crude product from ethanol/ether
aꢂorded the hydrochloride of the title compound (9) as white
needles in 86% yield, m.p. 222–224ꢁ (dec.) [lit.24 223–224ꢁ
(dec.)] (Found: C, 53ꢀ7; H, 6ꢀ0; N, 7ꢀ1%; M+ꢂ ꢂ (HCl+NH3),
148ꢀ0526. Calc. for C9H12ClNO2: C, 53ꢀ6; H, 6ꢀ0; N, 7ꢀ0%;
Calc. for C9H8O2: m/z, 148ꢀ0524). ꢀmax 3142, 2733, 2611,
(Found: M+ꢂ
,
334ꢀ1096. Calc. for C14H21ClO5P: M+ꢂ
,
300ꢀ1126). ꢀmax 2984, 2937, 2907, 1736, 1601, 1497, 1455,
1392, 1147, 1029, 889 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ18, t, J 7ꢀ1 Hz,
3H, POCH2CH3; 1ꢀ25, t, J 7ꢀ1 Hz, 3H, POCH2CH3; 1ꢀ27,
t, J 7ꢀ1 Hz, 3H; 3ꢀ92–4ꢀ10, m, 4H, P(OCH2CH3)2; 4ꢀ14–
4ꢀ26, m, 2H; 4ꢀ27, d, JH–P 23ꢀ8 Hz, 1H; 7ꢀ28–7ꢀ54, m, 5H.
13C n.m.r. ꢁ 14ꢀ01; 16ꢀ20, d, JC–P 5ꢀ1 Hz, POCH2CH3; 16ꢀ27,
d, JC–P 5ꢀ5 Hz, POCH2CH3; 52ꢀ26, d, JC–P 134ꢀ7 Hz; 61ꢀ76;
63ꢀ04, d, JC–P 7ꢀ2 Hz, POCH2CH3; 63ꢀ37, d, JC–P 6ꢀ7 Hz,
POCH2CH3; 127ꢀ91, d, JC–P 2ꢀ7 Hz; 128ꢀ47, d, JC–P 2ꢀ4 Hz;
129ꢀ61, d, JC–P 7ꢀ2 Hz; 130ꢀ95, d, JC–P 8ꢀ1 Hz; 167ꢀ60. Mass
spectrum m/z 300 (M, 6%), 254 (8), 227 (7), 196 (14), 152
(17), 118 (100), 105 (23), 91 (40), 77 (15), 69 (79).
1716, 1590, 1509, 1405, 1223, 1099, 948, 828 cmꢃ1 1H n.m.r.
.
(D2O) ꢁ 3ꢀ41, dd, J 7ꢀ4, 13ꢀ1 Hz, 1H; 3ꢀ64, dd, J 7ꢀ7,
13ꢀ1 Hz, 1H; 4ꢀ11, apparent t, J 7ꢀ5 Hz, 1H; 7ꢀ38–7ꢀ53, m,
5H. 13C n.m.r. (D2O) ꢁ 41ꢀ26; 48ꢀ85; 128ꢀ39; 128ꢀ97; 129ꢀ71;
134ꢀ63; 175ꢀ03. Mass spectrum m/z 148 (M ꢂ (HCl+NH3),
34%), 136 (28), 119 (100), 103 (84), 91 (92), 77 (45).
Ethyl Bromo(4-chlorophenyl)acetate (12)
Ethyl 2-(4-Chlorophenyl)-2-diethoxyphosphinyl-3-
phthalimidopropanoate (16)
A mixture of ethyl 4-chlorophenylacetate (10ꢀ0 g, 51 mmol)
and N-bromosuccinimide (11ꢀ5 g, 54 mmol) in carbon tetra-
chloride (100 ml) was heated to reꢁux by irradiation with a
200-W tungsten globe. Dibenzoyl peroxide (0ꢀ2 g) was then
added and irradiation continued for 2 h. The reaction mix-
ture was cooled, light petroleum (50 ml) was added and the
solid succinimide removed and washed with additional light
petroleum (30 ml). The combined ꢀltrates were concentrated
under reduced pressure and the residue was distilled to aꢂord
the title compound (12) (12ꢀ5 g, 89%) as a colourless oil, b.p.
80ꢁ/0ꢀ1 mm (lit.25 125ꢁ/5ꢀ0 mm) (Found: M+ꢂ, 275ꢀ9570.
Calc. for C10H10BrClO2: M+ꢂ, 275ꢀ9553). ꢀmax 2985, 1744,
A solution of (14) (3ꢀ84 g, 11ꢀ5 mmol) in tetrahydrofuran
(3 ml) was added dropwise to a stirring suspension of sodium
hydride (0ꢀ50 g of a 60% dispersion in oil, 12ꢀ50 mmol) in
tetrahydrofuran (40 ml) at room temperature under a nitrogen
atmosphere.
After 0ꢀ5 h,
a solution of N-bromomethyl-
phthalimide (3ꢀ0 g, 12ꢀ5 mmol) in tetrahydrofuran (20 ml) was
added and the reaction mixture was stirred overnight. The reac-
tion mixture was quenched with saturated aqueous ammonium
chloride solution (15 ml) and the tetrahydrofuran was removed
under reduced pressure. The reaction mixture was extracted
with ether (3ꢁ30 ml). The combined organic extracts were
washed with saturated sodium chloride solution (3ꢁ50 ml), dried
1594, 1491, 1445, 1369, 1324, 1300, 1216, 1092, 878 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ27, t, J 7ꢀ2 Hz, 3H; 4ꢀ24, q, J 7ꢀ1 Hz, 2H; 5ꢀ30,

818
R. H. Prager and K. Schafer
and evaporated. The residue was chromatographed on silica
gel, with dichloromethane/ethyl acetate (9 : 1) as eluent, to
aꢂord the ester (16) (3ꢀ51 g, 63%) as a white solid, m.p.
114–115ꢁ (Found: C, 55ꢀ9; H, 5ꢀ3; N, 3ꢀ0%; M+ꢂ, 493ꢀ1087.
2-[(2-Diethoxyphosphinyl-2-phenyl)ethylcarbamoyl]benzoic
Acid (19)
The acid (19) was prepared by the above procedure from
the ester (17) (0ꢀ50 g, 1ꢀ09 mmol) as a white hygroscopic
glass (0ꢀ37 g) in 84% yield, m.p. 78–80ꢁ; this compound
was used in the next step without any further puriꢀcation
C
23H25ClNO7P requires C, 55ꢀ9; H, 5ꢀ1; N, 2ꢀ8%; M+ꢂ
,
493ꢀ1057). ꢀmax 1778, 1721, 1593, 1495, 1346, 1260, 1195,
1096, 1050, 957, 907, 824 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ09, t, J 7ꢀ1 Hz,
(Found:
M
+ꢂ ꢂ OH, 387ꢀ1210. C20H23NO5P requires m/z,
3H, POCH2CH3; 1ꢀ18, t, J 7ꢀ1 Hz, 3H, POCH2CH3; 1ꢀ27,
t, J 7ꢀ2 Hz, 3H; 3ꢀ82–4ꢀ11, m, 4H, P(OCH2CH3)2; 4ꢀ28–
4ꢀ41, m, 2H; 4ꢀ55, dd, J 14ꢀ4, JH–P 17ꢀ5 Hz, 1H; 4ꢀ81, dd,
J 14ꢀ4, JH–P 6ꢀ2 Hz, 1H; 7ꢀ29–7ꢀ50, m, 4H; 7ꢀ66–7ꢀ81, m,
4H. 13C n.m.r. ꢁ 13ꢀ79; 16ꢀ05, d, JC–P 5ꢀ5 Hz, POCH2CH3;
16ꢀ12, d, JC–P 5ꢀ3 Hz, POCH2CH3; 40ꢀ55, d, JC–P 3ꢀ2 Hz;
58ꢀ00, d, JC–P 138ꢀ9 Hz; 62ꢀ41; 63ꢀ01, d, JC–P 7ꢀ5 Hz,
POCH2CH3; 63ꢀ71, d, JC–P 7ꢀ1 Hz, POCH2CH3; 123ꢀ27;
128ꢀ06, d, JC–P 2ꢀ6 Hz; 130ꢀ51, d, JC–P 5ꢀ6 Hz; 131ꢀ92;
132ꢀ38, d, JC–P 7ꢀ7 Hz; 133ꢀ90, d, JC–P 2ꢀ4 Hz; 133ꢀ98;
167ꢀ84; 169ꢀ86. Mass spectrum m/z 495/493 (M, 2/8%),
290/288 (1/3), 160 (100).
387ꢀ1236). ꢀmax 3450–2581(br), 1718, 1643, 1579, 1219,
1019, 966, 738 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ11, t, J 7ꢀ1 Hz, 3H,
POCH2CH3; 1ꢀ23, t, J 7ꢀ1 Hz, 3H, POCH2CH3; 3ꢀ60–3ꢀ75,
m, 1H; 3ꢀ90–3ꢀ99, m, 2H; 4ꢀ00–4ꢀ15, m, 4H, P(OCH2CH3)2;
7ꢀ29–7ꢀ49, m, 9H; 8ꢀ45, br s, 2H, OH and NH (D2O exch.).
13C n.m.r. ꢁ 16ꢀ13, d, JC–P 6ꢀ1 Hz, POCH2CH3; 16ꢀ24, d,
JC–P 6ꢀ0 Hz, POCH2CH3; 40ꢀ53; 43ꢀ61, d, JC–P 136ꢀ5 Hz;
62ꢀ71, d, JC–P 7ꢀ2 Hz, POCH2CH3; 63ꢀ37, d, JC–P 7ꢀ1 Hz,
POCH2CH3; 127ꢀ76; 128ꢀ77, d, JC–P 3ꢀ8 Hz; 128ꢀ93, d,
JC–P 2ꢀ9 Hz; 129ꢀ36; 129ꢀ41, d, JC–P 6ꢀ4 Hz; 129ꢀ93; 131ꢀ10;
131ꢀ87; 133ꢀ96, d, JC–P 6ꢀ7 Hz; 136ꢀ91; 168ꢀ52; 170ꢀ55. Mass
spectrum m/z 387 (M ꢂ OH, 41%), 249 (19), 228 (30), 212
(11), 172 (20), 160 (100), 104 (41), 91 (25), 76 (23).
Ethyl 2-Diethoxyphosphinyl-2-phenyl-3-
phthalimidopropanoate (17)
Hydrochloride Salt of 2-Amino-1-(4-chlorophenyl)-
ethylphosphonic Acid (20)
The title compound (17) was prepared as above from (15)
(3ꢀ0 g, 10ꢀ0 mmol). Puriꢀcation by column chromatography
on silica gel, with dichloromethane/ethyl acetate (4 : 1) as
eluent, gave the ester (17) (2ꢀ93 g, 64%) as a white solid,
A
mixture of the acid (18) (0ꢀ26 g, 0ꢀ59 mmol) and
8 M hydrochloric acid (20 ml) was heated under reꢁux for
12 h. After cooling, the reaction mixture was washed with
dichloromethane (3ꢁ20 ml) and concentrated under reduced
pressure. The residue was recrystallized from ethanol/ether to
aꢂord the hydrochloride of the title compound (20) (0ꢀ13 g,
81%) as white crystals, m.p. 290–293ꢁ (dec.) (Found: C, 35ꢀ5;
H, 4ꢀ7; N, 5ꢀ4. C8H12Cl2NO3P requires C, 35ꢀ3; H, 4ꢀ5;
N, 5ꢀ2%). ꢀmax 3420–2506(br), 1643, 1589, 1540, 1492, 1240,
m.p. 92–94ꢁ (Found: C, 59ꢀ7; H, 5ꢀ6; N, 3ꢀ2%; M+ꢂ
,
459ꢀ1465.
1200, 1164, 1050, 967, 950, 753 cmꢃ1
C
23H26NO7P requires C, 60ꢀ1; H, 5ꢀ7; N, 3ꢀ1%;
M+ꢂ, 459ꢀ1447). ꢀmax 1777, 1720, 1501, 1398, 1332, 1260,
.
1H n.m.r. ꢁ 1ꢀ07, t,
J 7ꢀ1 Hz, 3H, POCH2CH3; 1ꢀ16, t, J 7ꢀ1 Hz, 3H, POCH2CH3;
1ꢀ30, t, J 7ꢀ1 Hz, 3H; 3ꢀ82–4ꢀ11, m, 4H, P(OCH2CH3)2;
4ꢀ31–4ꢀ46, m, 2H; 4ꢀ58, dd, J 14ꢀ4, JH–P 17ꢀ5 Hz, 1H; 4ꢀ93,
dd, J 14ꢀ4, JH–P 6ꢀ2 Hz, 1H; 7ꢀ32–7ꢀ59, m, 5H; 7ꢀ68–7ꢀ81, m,
4H. 13C n.m.r. ꢁ 13ꢀ57; 15ꢀ80, d, JC–P 6ꢀ7 Hz, POCH2CH3;
15ꢀ89, d, JC–P 6ꢀ6 Hz, POCH2CH3; 40ꢀ59, d, JC–P 3ꢀ6 Hz;
58ꢀ19, d, JC–P 140ꢀ0 Hz; 62ꢀ06; 62ꢀ82, d, JC–P 7ꢀ4 Hz,
POCH2CH3; 63ꢀ43, d, JC–P 7ꢀ0 Hz, POCH2CH3; 123ꢀ01;
127ꢀ67, d, JC–P 3ꢀ2 Hz; 127ꢀ80, d, JC–P 2ꢀ3 Hz; 128ꢀ75, d,
JC–P 5ꢀ0 Hz; 131ꢀ81; 133ꢀ62; 133ꢀ76; 167ꢀ67; 170ꢀ04. Mass
spectrum m/z 459 (M, 31%), 413 (11), 254 (14), 181 (9), 160
(100), 147 (12), 103 (22), 77 (16).
1196, 1171, 1137, 1014, 910, 832, 821, 718 cmꢃ1
.
1H n.m.r.
(D2O) ꢁ 3ꢀ33–3ꢀ45, m, 2H; 3ꢀ55–3ꢀ68, m, 1H; 7ꢀ34–7ꢀ45,
m, 4H. 13C n.m.r. (D2O) ꢁ 40ꢀ21; 43ꢀ69, d, JC–P 131ꢀ1 Hz;
129ꢀ32, d, JC–P 3ꢀ2 Hz; 130ꢀ60, d, JC–P 5ꢀ7 Hz; 132ꢀ41, d,
JC–P 7ꢀ7 Hz; 133ꢀ56, d, JC–P 2ꢀ5 Hz.
Hydrochloride Salt of 2-Amino-1-phenylethylphosphonic
Acid (21)
The acid (19) was hydrolysed as above to yield the hydrochlo-
ride salt of the title compound (21) as white crystals (73%),
m.p. 277–280ꢁ (dec.) [lit.27 274–276ꢁ (dec.)] (Found: C, 40ꢀ6;
H, 5ꢀ5; N, 6ꢀ2. Calc. for C8H13ClNO3P: C, 40ꢀ4; H, 5ꢀ5;
N, 6ꢀ2%). ꢀmax 3342–2584(br), 1683, 1569, 1239, 1172, 1088,
2H; 3ꢀ49–3ꢀ69, m, 1H; 7ꢀ39–7ꢀ44, m, 5H. 13C n.m.r. (D2O)
ꢁ 39ꢀ99; 43ꢀ76, d, JC–P 133ꢀ7 Hz; 128ꢀ54, d, JC–P 3ꢀ0 Hz;
129ꢀ15, d, JC–P 5ꢀ9 Hz; 129ꢀ43, d, JC–P 2ꢀ3 Hz; 132ꢀ72, d,
JC–P 7ꢀ3 Hz.
2-[(2-(4-Chlorophenyl)-2-diethoxyphosphinyl)ethylcarbamoyl]-
benzoic Acid (18)
To a solution of the ester (16) (0ꢀ50 g, 1ꢀ02 mmol) in
ethanol (12 ml) was added a solution of potassium hydroxide
(0ꢀ24 g, 4ꢀ08 mmol) in water (3 ml), and the mixture reꢁuxed
for 1 h. On cooling, the reaction mixture was extracted with
ether (3ꢁ20 ml), acidiꢀed with 2 M hydrochloric acid and
extracted with ethyl acetate (3ꢁ20 ml). The combined organic
extracts were dried, ꢀltered and evaporated under reduced
pressure to aꢂord the acid (18) (0ꢀ35 g, 79%) as a white
hygroscopic glass which was used in the next step without
1015, 981, 834, 791 cmꢃ1
.
1H n.m.r. (D2O) ꢁ 3ꢀ29–3ꢀ44, m,
(Diethoxyphospinyl)phenylacetic Acid (22)
any further puriꢀcation, m.p. 111–114ꢁ (Found:
M
+ꢂ ꢂ OH,
421ꢀ0875.
771 cmꢃ1
C
20H2235ClNO5P requires m/z, 421ꢀ0846). ꢀmax
A mixture of (15) (0ꢀ3 g, 1ꢀ0 mmol) and potassium hydrox-
ide (0ꢀ17 g, 3ꢀ0 mmol) in ethanol/water (15 ml of 4 : 1 v/v)
was reꢁuxed for 1 h. The reaction mixture was concentrated
and redissolved in water (7 ml), acidiꢀed with 3 M hydrochloric
acid and extracted with ethyl acetate (3ꢁ10 ml). The com-
bined organic fractions were dried, ꢀltered and concentrated
to dryness to aꢂord the acid (22) as a colourless oil (0ꢀ21 g,
77%). ꢀmax 3405, 1726, 1492, 1451, 1389, 1229, 1159, 1024,
3443–2623(br), 1717, 1644, 1597, 1544, 1216, 1014, 963,
.
1H n.m.r. ꢁ 1ꢀ16, t, J 7ꢀ2 Hz, 3H, POCH2CH3;
1ꢀ25, t, J 7ꢀ2 Hz, 3H, POCH2CH3; 3ꢀ61–3ꢀ75, m, 1H; 3ꢀ88–
3ꢀ99, m, 2H; 4ꢀ02–4ꢀ13, m, 4H, P(OCH2CH3)2; 7ꢀ26–7ꢀ35, m,
4H; 7ꢀ42–7ꢀ47, m, 4H; 8ꢀ50, br s, 2H, OH and NH (D2O exch.).
13C n.m.r. ꢁ 16ꢀ24, d, JC–P 5ꢀ5 Hz, POCH2CH3; 16ꢀ30, d,
JC–P 5ꢀ6 Hz, POCH2CH3; 40ꢀ47; 42ꢀ98, d, JC–P 136ꢀ6 Hz;
62ꢀ85, d, JC–P 7ꢀ1 Hz, POCH2CH3; 63ꢀ43, d, JC–P 7ꢀ1 Hz,
POCH2CH3; 127ꢀ68; 128ꢀ97, d, JC–P 3ꢀ8 Hz; 129ꢀ87; 130ꢀ08;
130ꢀ68, d, JC–P 6ꢀ5 Hz; 131ꢀ24; 131ꢀ99; 132ꢀ64, d, JC–P 7ꢀ2 Hz;
133ꢀ73, d, JC–P 3ꢀ4 Hz; 136ꢀ79; 168ꢀ44; 170ꢀ51. Mass spec-
trum m/z 423/421 (M ꢂ OH, 13/38%), 285/283 (7/13), 264/262
(9/25), 232/230 (6/11), 208/206 (6/18), 160 (100), 127/125
(7/21), 76 (30).
969 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ12, t, J 7ꢀ1 Hz, 3H; 1ꢀ20, t, J 7ꢀ1 Hz,
3H; 3ꢀ95–4ꢀ09, m, 4H; 4ꢀ30, d, JH–P 23ꢀ6 Hz, 1H; 7ꢀ29–7ꢀ49,
m, 5H; 8ꢀ18, br s, 1H, OH (D2O exch.). 13C n.m.r. ꢁ 16ꢀ05, d,
JC–P 5ꢀ6 Hz, OCH2CH3; 16ꢀ19, d, JC–P 5ꢀ5 Hz, OCH2CH3;
52ꢀ13, d, JC–P 136ꢀ2 Hz; 63ꢀ67, d, JC–P 7ꢀ0 Hz; 64ꢀ04, d,
JC–P 6ꢀ7 Hz; 127ꢀ95, d, JC–P 2ꢀ8 Hz; 128ꢀ48, d, JC–P 2ꢀ3 Hz;
129ꢀ77, d, JC–P 6ꢀ3 Hz; 130ꢀ95, d, JC–P 8ꢀ6 Hz; 169ꢀ23.

Potential GABA Receptor Antagonists. X
819
B
Hydrochloride Salt of 2-Amino-1-(4-chlorophenyl)ethanesulfonic
Acid (23)
J 6ꢀ6 Hz, 1H, NH (D2O exch.); 7ꢀ24–7ꢀ49, m, 8H; 7ꢀ87, d,
J 7ꢀ7 Hz, 1H; 10ꢀ65, br s, 2H, OH (D2O exch.). 13C n.m.r. ꢁ
42ꢀ91; 50ꢀ15; 127ꢀ81; 128ꢀ08; 128ꢀ91; 129ꢀ07; 129ꢀ71; 130ꢀ09;
130ꢀ94; 132ꢀ81; 134ꢀ09; 136ꢀ06; 170ꢀ53; 170ꢀ81; 177ꢀ60. Mass
spectrum m/z 277 (M ꢂ 2H2O, 12%), 160 (49), 148 (46), 104
(100), 76 (81).
A solution of 1-(4-chlorophenyl)-2-nitroethylene (2ꢀ98 g,
16ꢀ3 mmol) in dioxan (20 ml) was added dropwise to a stirring
solution of sodium metabisulꢀte (2ꢀ74 g, 14ꢀ4 mmol) in water
(20 ml), and the mixture was stirred at room temperature
overnight. The reaction mixture was extracted with ether
(3ꢁ25 ml) and evaporated to dryness under reduced pressure.
The residue was sequentially extracted and recrystallized from
hot ethanol to furnish sodium 1-(4-chlorophenyl)-2-nitroethane-
sulfonate as a white solid (3ꢀ61 g, 77%), m.p. >325ꢁ. ꢀmax
3464–3205(br), 3025, 1576, 1553, 1496, 1430, 1388, 1253,
2-(4-Chlorophenyl)-3-phthalimidopropanohydroxamic Acid (28)
The acid (26) (1ꢀ0 g, 2ꢀ88 mmol) was reꢁuxed in thionyl
chloride (10 ml) for 2 h under an atmosphere of nitrogen.
The solvent was removed under vacuum to aꢂord 2-(4-chloro-
phenyl)-3-phthalimidopropanoyl chloride as a pale yellow oil
(0ꢀ98 g, 98%), which crystallized on standing. The crude acid
chloride was used immediately in the next step without any
further puriꢀcation. ꢀmax 1776, 1714, 1126, 1088, 1034, 993,
1191 cmꢃ1
.
1H n.m.r. (D2O) ꢁ 4ꢀ93, apparent t, J 6ꢀ4 Hz, 1H;
5ꢀ11, dd, J 6ꢀ3, 14ꢀ0 Hz, 1H; 5ꢀ30, dd, J 6ꢀ1, 14ꢀ0 Hz, 1H;
7ꢀ65–7ꢀ70, m, 4H. 13C n.m.r. (D2O) ꢁ 62ꢀ44; 75ꢀ45; 129ꢀ06;
130ꢀ01; 131ꢀ27; 134ꢀ50.
951, 786, 717 cmꢃ1 1H n.m.r. (CDCl3/triꢁuoroacetic acid) ꢁ
.
4ꢀ17, dd, J 8ꢀ7, 14ꢀ1 Hz, 1H; 4ꢀ31, dd, J 7ꢀ1, 14ꢀ1 Hz, 1H;
4ꢀ71, dd, J 7ꢀ2, 8ꢀ7 Hz, 1H; 7ꢀ24–7ꢀ35, m, 4H; 7ꢀ78–7ꢀ88, m,
4H. 13C n.m.r. (CDCl3/triꢁuoroacetic acid) ꢁ 39ꢀ90; 59ꢀ69;
124ꢀ05; 129ꢀ69; 130ꢀ08; 130ꢀ98; 131ꢀ04; 134ꢀ95; 135ꢀ38;
168ꢀ73; 173ꢀ00.
A solution of the sulfonate (0ꢀ35 g, 1ꢀ22 mmol) in a mixture
of ethanol/water (30 ml of 1 : 2 v/v) was hydrogenated over
Adams’ catalyst (100 mg) at 4 atm for 20 h. The reaction
mixture was ꢀltered, acidiꢀed to pH 1 with concentrated
hydrochloric acid, and evaporated to dryness. The resul-
tant solid was extracted with concentrated hydrochloric acid
(3ꢁ5 ml). The combined acid extracts were concentrated under
reduced pressure to give a solid residue which was recrystallized
from aqueous ethanol to aꢂord the title compound (23) (0ꢀ18 g,
55%) as grey platelets, m.p. >325ꢁ. The product lost HCl on
vacuum drying, as indicated by microanalysis (Found: C, 40ꢀ7;
H, 4ꢀ4; N, 6ꢀ0. C8H10ClNO3S requires C, 40ꢀ7; H, 4ꢀ3; N,
5ꢀ9%). ꢀmax 3174, 3036, 2623, 1641, 1596, 1550, 1494, 1415,
Freshly distilled triethylamine (1ꢀ57 ml, 11ꢀ30 mmol) was
added to a solution of hydroxylamine hydrochloride (0ꢀ79 g,
11ꢀ30 mmol) in dry dichloromethane (50 ml) at 0ꢁ under a nitro-
gen atmosphere. After 0ꢀ5 h, a solution of 2-(4-chlorophenyl)-
3-phthalimidopropanoyl chloride (0ꢀ98 g, 2ꢀ82 mmol) in dry
dichloromethane (3 ml) was added dropwise, and the reaction
mixture was stirred for 1 h at 0ꢁ and then for 2 h at room
temperature. The reaction mixture was poured into 2 M
hydrochloric acid (20 ml). The organic layer was washed with
2 M hydrochloric acid (3ꢁ40 ml) and 10% sodium carbonate
solution, dried, ꢀltered and concentrated under vacuum to
give a crude solid which was recrystallized from ethanol to
aꢂord the hydroxamic acid (28) as white crystals (0ꢀ54 g,
1259, 1049, 823 cmꢃ1
.
1H n.m.r. (D2O) ꢁ 3ꢀ12, dd, J 6ꢀ3,
12ꢀ8 Hz, 1H; 3ꢀ42, dd, J 6ꢀ1, 12ꢀ6 Hz, 1H; 3ꢀ91, apparent t,
J 6ꢀ3 Hz, 1H; 7ꢀ29–7ꢀ34, m, 4H. 13C n.m.r. (D2O) ꢁ 39ꢀ61;
61ꢀ21; 128ꢀ38; 129ꢀ80; 130ꢀ24; 134ꢀ04.
54%), m.p. 204–207ꢁ (Found: C, 59ꢀ2; H, 3ꢀ9; N, 8ꢀ3%; M+ꢂ
,
2-[(2-Carboxy-2-(4-chlorophenyl))ethylcarbamoyl]-
benzoic Acid (26)
344ꢀ0584. C17H13ClN2O4 requires C, 59ꢀ2; H, 3ꢀ8; N, 8ꢀ1%;
M+ꢂ, 344ꢀ0563). ꢀmax 3438, 3291, 3100, 1769, 1705, 1667,
A mixture of the ester (6) (3ꢀ0 g, 7ꢀ0 mmol) and solid
potassium hydroxide (1ꢀ17 g, 21ꢀ0 mmol) in ethanol/water
(50 ml of 4 : 1 v/v) was reꢁuxed for 1 h. The reaction mixture
was cooled and concentrated under reduced pressure. The
resulting residue was dissolved in water (10 ml) and washed
with ether (3ꢁ10 ml). The aqueous fraction was acidiꢀed
with 2 M hydrochloric acid and extracted with ethyl acetate
(4ꢁ15 ml). The combined organic extracts were dried, ꢀltered
and concentrated under vacuum to aꢂord the acid (26) as a
colourless hygroscopic glass (2ꢀ04 g, 84%); this was used in
the next step without any further puriꢀcation, m.p. 103–105ꢁ
1631, 1588, 1491, 1396, 1067 cmꢃ1
.
1H n.m.r. (CDCl3/tri-
ꢁuoroacetic acid) ꢁ 4ꢀ13, dd, J 6ꢀ3, 13ꢀ6 Hz, 1H; 4ꢀ21, dd,
J 7ꢀ3, 12ꢀ6 Hz, 1H; 4ꢀ37, dd, J 7ꢀ4, 12ꢀ6 Hz, 1H; 7ꢀ32,
s, 4H; 7ꢀ77–7ꢀ85, m, 4H. 13C n.m.r. (CDCl3/triꢁuoroacetic
acid) ꢁ 40ꢀ15; 46ꢀ52; 124ꢀ19; 129ꢀ41; 129ꢀ58; 130ꢀ69; 131ꢀ90;
135ꢀ28; 135ꢀ34; 169ꢀ81; 170ꢀ22. Mass spectrum m/z 346/344
(M, 1/4%), 313/311 (29/65), 312 (21), 285/283 (38/48), 284
(45), 160 (100), 104 (66), 77 (85), 76 (80).
2-Phenyl-3-phthalimidopropanohydroxamic Acid (29)
(Found:
M
+ꢂ ꢂ 2H2O, 311ꢀ0345. C17H1035ClNO3 requires
The hydroxamic acid (29) was prepared as above from
(27). Recrystallization of the crude residue from ethanol
aꢂorded the title compound (29) as white crystals (52%),
m/z, 311ꢀ0349). ꢀmax 3355, 1718, 1633, 1588, 1550, 1273,
1179, 1074, 980 cmꢃ1 1H n.m.r. (CDCl3/triꢁuoroacetic acid)
.
ꢁ 3ꢀ70–3ꢀ76, m, 1H; 3ꢀ87–3ꢀ91, m, 1H; 4ꢀ30, dd, J 4ꢀ6,
10ꢀ2 Hz, 1H; 6ꢀ97, t, J 6ꢀ6 Hz, 1H, NH (D2O exch.); 7ꢀ21–
7ꢀ67, m, 7H; 8ꢀ08, d, J 7ꢀ6 Hz, 1H; 10ꢀ91, br s, 2H, OH (D2O
exch.). 13C n.m.r. (CDCl3/triꢁuoroacetic acid) ꢁ 43ꢀ01; 49ꢀ07;
127ꢀ94; 129ꢀ29; 129ꢀ49; 129ꢀ83; 130ꢀ98; 131ꢀ51; 133ꢀ01;
134ꢀ08; 134ꢀ64; 135ꢀ95; 171ꢀ27; 173ꢀ35; 178ꢀ56. Mass spec-
trum m/z 313/311 (M ꢂ 2H2O, 6/16%), 184/182 (11/36), 160
(53), 149/147 (13/57), 148 (58), 127/125 (15/48), 104 (100),
76 (89).
m.p. 209–210ꢁ (Found: C, 65ꢀ9; H, 4ꢀ4; N, 9ꢀ0%; M+ꢂ
,
310ꢀ0959.
C
17H14N2O4 requires C, 65ꢀ8; H, 4ꢀ6; N, 9ꢀ0%;
M+ꢂ, 310ꢀ0953). ꢀmax 3466, 3317, 1774, 1715, 1647, 1494,
1400, 1326, 1254, 1178, 954 cmꢃ1
.
1H n.m.r. (CDCl3/tri-
ꢁuoroacetic acid) ꢁ 4ꢀ15, dd, J 6ꢀ3, 13ꢀ65 Hz, 1H; 4ꢀ23, dd,
J 7ꢀ4, 12ꢀ6 Hz, 1H; 4ꢀ37, dd, J 7ꢀ4, 12ꢀ6 Hz, 1H; 7ꢀ32, s, 5H;
7ꢀ75–7ꢀ87, m, 4H. 13C n.m.r. (CDCl3/triꢁuoroacetic acid) ꢁ
40ꢀ15; 47ꢀ28; 124ꢀ15; 128ꢀ04; 129ꢀ15; 129ꢀ41; 130ꢀ71; 133ꢀ28;
135ꢀ30; 170ꢀ00; 170ꢀ74. Mass spectrum m/z 310 (M, 7%),
277 (69), 249 (56), 160 (90), 132 (50), 118 (69), 104 (100), 77
(82), 76 (74).
2-[(2-Carboxy-2-phenyl)ethylcarbamoyl]benzoic Acid (27)
The acid (27) was prepared by treating (7) (1ꢀ0 g, 2ꢀ53 mmol)
in a manner analogous to that above. The title compound (27)
was isolated as a colourless hygroscopic glass (0ꢀ70 g, 88%),
m.p. 81–84ꢁ; this was used in the next step without any further
Hydrochloride Salt of 3-Amino-2-(4-chlorophenyl)-
propanohydroxamic Acid (30)
A mixture of the hydroxamic acid (28) (0ꢀ40 g, 1ꢀ16 mmol),
hydrazine monohydrate (75ꢀ49 mg, 1ꢀ51 mmol) and ethanol
(20 ml) was heated at reꢁux for 2 h. The reaction mixture was
cooled and left to stand at room temperature overnight, during
which time a white solid precipitated. The solid was collected
puriꢀcation (Found:
M
+ꢂ ꢂ 2H2O, 277ꢀ0744. C17H11NO3
requires m/z, 277ꢀ0738). ꢀmax 3300, 1719, 1647, 1594, 1540,
1273, 1172, 1081, 984 cmꢃ1
3ꢀ77–3ꢀ82, m, 1H; 4ꢀ21, dd, J 4ꢀ2, 10ꢀ6 Hz, 1H; 6ꢀ76, t,
.
1H n.m.r. ꢁ 3ꢀ55–3ꢀ61, m, 1H;

820
R. H. Prager and K. Schafer
and washed with ethanol (10 ml). The ethanolic extracts were
combined, acidiꢀed with 3 M hydrochloric acid and concentrated
to half of their original volume. The precipitate was collected
by vacuum ꢀltration and washed with ethanol (10 ml). The
ethanolic ꢀltrate was evaporated to dryness to give a white
solid which was recrystallized from aqueous ethanol/ether to
aꢂord the title compound (30) (0ꢀ18 g, 62%), m.p. 222–224ꢁ
(dec.) (Found: C, 42ꢀ9; H, 4ꢀ9; N, 11ꢀ1. C9H12Cl2N2O2
requires C, 43ꢀ0; H, 4ꢀ8; N, 11ꢀ2%). ꢀmax 3448, 3257, 1710,
from ethanol/ether aꢂorded the hydrochloride of compound
(34) as a white solid (0ꢀ95 g, 84%), m.p. 152–155ꢁ (lit.15
155–156ꢁ) (Found: C, 51ꢀ3; H, 6ꢀ2; N, 3ꢀ8%; M+ꢂ ꢂ HCl,
313ꢀ1110. Calc. for C15H21Cl2NO4: C, 51ꢀ4; H, 6ꢀ1; N, 4ꢀ0%;
C
15H20ClNO4, m/z, 313ꢀ1080). ꢀmax 3350, 1730, 1495, 1257,
1136, 1013, 829 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ24, t, J 7ꢀ2 Hz, 6H; 2ꢀ75,
t, J 7ꢀ7 Hz, 2H; 2ꢀ99, t, J 7ꢀ6 Hz, 2H; 4ꢀ22, q, J 7ꢀ2 Hz,
4H; 7ꢀ28, d, J 8ꢀ6 Hz, 2H; 7ꢀ36, d, J 8ꢀ6 Hz, 2H; 8ꢀ33, br
s, 3H, NH3 (D2O exch.). 13C n.m.r. ꢁ 13ꢀ93; 33ꢀ02; 36ꢀ50;
+
1642, 1625, 1518, 1497, 1330, 1290, 970, 737 cmꢃ1
.
1H n.m.r.
61ꢀ16; 62ꢀ47; 128ꢀ77; 129ꢀ37; 134ꢀ11; 134ꢀ21; 169ꢀ75. Mass
spectrum m/z 315/313 (M ꢂ HCl, 4/13%), 269/267 (24/47),
226/224 (53/100), 223/221 (35/71), 196/194 (52/62), 139/137
(53/91), 117/115 (21/40).
(D2O) ꢁ 3ꢀ39, dd, J 7ꢀ2, 13ꢀ0 Hz, 1H; 3ꢀ57, dd, J 7ꢀ2,
12ꢀ9 Hz, 1H; 3ꢀ89, apparent t, J 7ꢀ2 Hz, 1H; 7ꢀ32–7ꢀ39, m,
4H. 13C n.m.r. (D2O) ꢁ 40ꢀ97; 45ꢀ60; 129ꢀ63; 129ꢀ76; 133ꢀ09;
134ꢀ31; 169ꢀ40.
Hydrochloride Salt of Diethyl (2-Aminoethyl)-
phenylpropanedioate (35)
Hydrochloride Salt of 3-Amino-2-phenylpropanohydroxamic
Acid (31)
The ester (33) (1ꢀ0 g, 3ꢀ64 mmol) was hydrogenated as
above to yield the hydrochloride of compound (35) as a white
solid (0ꢀ78 g, 68%), after recrystallization of the crude residue
from ethanol/ether, m.p. 107–110ꢁ (lit.15 111–113ꢁ) (Found:
C, 56ꢀ8; H, 7ꢀ1; N, 4ꢀ3%; M+ꢂ ꢂ HCl, 279ꢀ1496. Calc. for
Compound (31) was synthesized as above from (29). Recrys-
tallization of the crude solid from aqueous ethanol/ether aꢂorded
the title compound (31) (89 mg, 64%) as a white powder,
m.p. 169–172ꢁ (dec.) (Found: C, 49ꢀ6; H, 5ꢀ7; N, 12ꢀ6.
C9H13ClN2O2 requires C, 49ꢀ9; H, 6ꢀ0; N, 12ꢀ9%). ꢀmax
3262, 1705, 1641, 1624, 1515, 1418, 1248, 1156, 1098, 987,
C15H22ClNO4: C, 57ꢀ1; H, 7ꢀ0; N, 4ꢀ4%; C15H21NO4: m/z,
279ꢀ1470). ꢀmax 3350, 1734, 1604, 1491, 1250, 1136, 1029,
919 cmꢃ1
.
1H n.m.r. (D2O) ꢁ 3ꢀ40, dd, J 7ꢀ2, 12ꢀ9 Hz, 1H;
861 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ24, t, J 7ꢀ2 Hz, 6H; 2ꢀ73, t, J 7ꢀ6 Hz,
3ꢀ58, dd, J 7ꢀ2, 12ꢀ9 Hz, 1H; 3ꢀ89, apparent t, J 7ꢀ2 Hz, 1H;
7ꢀ35–7ꢀ44, m, 5H. 13C n.m.r. (D2O) ꢁ 41ꢀ05; 46ꢀ19; 128ꢀ31;
129ꢀ06; 129ꢀ90; 133ꢀ47; 169ꢀ79.
2H; 2ꢀ98, t, J 7ꢀ5 Hz, 2H; 4ꢀ22, q, J 7ꢀ2 Hz, 4H; 7ꢀ27–7ꢀ33,
m, 5H; 8ꢀ33, br s, 3H, NH3 (D2O exch.). 13C n.m.r. ꢁ 13ꢀ94;
+
33ꢀ54; 36ꢀ59; 61ꢀ85; 62ꢀ28; 127ꢀ71; 128ꢀ00; 128ꢀ63; 135ꢀ80;
170ꢀ03. Mass spectrum m/z 279 (M ꢂ HCl, 25%), 233 (56),
190 (100), 187 (62), 176 (31), 160 (80), 131 (71), 117 (70), 103
(94), 91 (40), 77 (76).
Diethyl (4-Chlorophenyl)cyanomethylpropanedioate (32)
Diethyl (4-chlorophenyl)propanedioate (6ꢀ75 g, 25 mmol)
was added dropwise to a stirring suspension of sodium hydride
(1ꢀ0 g of a 60% dispersion in mineral oil, 25 mmol) in anhydrous
tetrahydrofuran (120 ml) under nitrogen at room temperature.
After 0ꢀ5 h, bromoacetonitrile (1ꢀ75 ml, 25 mmol) was added
slowly to the reaction mixture and stirring was continued for
20 h. The reaction mixture was quenched with saturated aque-
ous ammonium chloride solution (20 ml). The aqueous fraction
was extracted with ether (3ꢁ20 ml). The tetrahydrofuran
solution and ethereal extracts were combined, washed with
saturated aqueous sodium chloride solution (2ꢁ100 ml), dried,
ꢀltered and concentrated under reduced pressure. The residue
was puriꢀed by Kugelrohr distillation to give the title compound
(32) as a colourless oil (6ꢀ31 g, 82%), b.p. 140–143ꢁ/0ꢀ1 mm
(lit.15 155–160ꢁ/0ꢀ4 mm) (Found: M+ꢂ, 309ꢀ0719. Calc. for
Hydrochloride Salt of 4-Amino-2-(4-chlorophenyl)-
butanoic Acid (36)
The ester (34) was hydrolysed by the method of Leonard.15
A mixture of (34) (1ꢀ0 g, 2ꢀ87 mmol) and 8 M hydrochloric
acid (30 ml) was heated at reꢁux for 16 h. Puriꢀcation of
the residue by recrystallization from ethanol/ether aꢂorded the
hydrochloride of the amino acid (36) as white needles (0ꢀ62 g,
87%), m.p. 197–200ꢁ (dec.) [lit.15 198–199ꢁ (dec.)] (Found: C,
47ꢀ6; H, 5ꢀ0; N, 5ꢀ4%; M+ꢂ ꢂ (HCl+H2O), 195ꢀ0440. Calc.
for C10H13Cl2NO2: C, 48ꢀ0; H, 5ꢀ2; N, 5ꢀ6%; C10H10ClNO,
m/z, 195ꢀ0451). ꢀmax 3246–2500(br), 1724, 1596, 1491, 1414,
1279, 1243, 1130, 773 cmꢃ1
.
1H n.m.r. (D2O) ꢁ 2ꢀ08–2ꢀ37, m,
C
15H16ClNO4: M+ꢂ, 309ꢀ0767). ꢀmax 2257, 1733, 1603, 1503,
2H; 2ꢀ82–2ꢀ97, m, 2H; 3ꢀ75, apparent t, J 7ꢀ7 Hz, 1H; 7ꢀ26, d,
J 8ꢀ5 Hz, 2H; 7ꢀ33, d, J 8ꢀ5 Hz, 2H. 13C n.m.r. (D2O) ꢁ 29ꢀ85;
37ꢀ69; 47ꢀ94; 129ꢀ24; 129ꢀ58; 133ꢀ31; 136ꢀ14; 176ꢀ62. Mass
spectrum m/z 197/195 (M ꢂ (HCl+H2O), 22/65%), 154/152
(15/64), 127/125 (5/15), 117 (100), 103 (12), 91 (11), 77 (8).
1449, 1390, 1244, 1095, 1045, 937, 731 cmꢃ1
.
1H n.m.r. ꢁ
1ꢀ29, t, J 7ꢀ2 Hz, 6H; 3ꢀ23, s, 2H; 4ꢀ30–4ꢀ35, m, 4H; 7ꢀ29,
d, J 8ꢀ7 Hz, 2H; 7ꢀ38, d, J 8ꢀ5 Hz, 2H. 13C n.m.r. ꢁ 13ꢀ91;
26ꢀ06; 60ꢀ12; 63ꢀ15; 116ꢀ34; 128ꢀ80; 128ꢀ97; 133ꢀ35; 134ꢀ90;
167ꢀ82. Mass spectrum m/z 311/309 (M, 2/7%), 238/236
(9/22), 239/237 (6/18), 211/209 (9/30), 210/208 (19/15),
166/164 (13/22), 127/125 (42/100).
Hydrochloride Salt of 4-Amino-2-phenylbutanoic Acid (37)
Compound (35) (1ꢀ0 g, 3ꢀ17 mmol) was hydrolysed/de-
carboxylated as above. Recrystallization from ethanol/ether
yielded the amino acid (37) as a white powder (0ꢀ61 g, 90%),
m.p. 194–197ꢁ (dec.) [lit.15 193–195ꢁ (dec.)] (Found: C, 55ꢀ8;
H, 6ꢀ4; N, 6ꢀ4%; M+ꢂ ꢂ (HCl+H2O), 161ꢀ0861. Calc. for
Diethyl (Cyanomethyl)phenylpropanedioate (33)
Diethyl phenylpropanedioate was alkylated as above. Puriꢀ-
cation of the crude residue by Kugelrohr distillation aꢂorded the
ester (33) as a colourless oil (5ꢀ75 g, 84%), b.p. 130–135ꢁ/1ꢀ0 mm
(lit.15 136–138ꢁ/1ꢀ0 mm) (Found: M+ꢂ, 275ꢀ1172. Calc. for
C
10H14ClNO2: C, 55ꢀ7; H, 6ꢀ6; N, 6ꢀ5%; C10H11NO, m/z,
161ꢀ0841). ꢀmax 3250–2520(br), 1722, 1616, 1596, 1495, 1400,
C
15H17NO4: M+ꢂ, 275ꢀ1156). ꢀmax 2257, 1732, 1606, 1503,
1242, 1169, 854, 749 cmꢃ1
.
1H n.m.r. (D2O) ꢁ 2ꢀ11–2ꢀ37,
1457, 1391, 1244, 1045, 936, 734 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ29, t,
m, 2H; 2ꢀ81–2ꢀ97, m, 2H; 3ꢀ76, apparent t, J 7ꢀ6 Hz, 1H;
7ꢀ29–7ꢀ38, m, 5H. 13C n.m.r. (D2O) ꢁ 29ꢀ91; 37ꢀ69; 48ꢀ52;
128ꢀ07; 128ꢀ25; 129ꢀ40; 133ꢀ61; 177ꢀ01. Mass spectrum m/z
161 (M ꢂ (HCl+H2O), 100%), 117 (90), 104 (12), 91 (27),
77 (9).
J 7ꢀ2 Hz, 6H; 3ꢀ24, s, 2H; 4ꢀ26–4ꢀ37, m, 4H; 7ꢀ33–7ꢀ40, m,
5H. 13C n.m.r. ꢁ 13ꢀ92; 26ꢀ19; 60ꢀ80; 62ꢀ95; 116ꢀ68; 127ꢀ33;
128ꢀ60; 128ꢀ78; 135ꢀ09; 168ꢀ19. Mass spectrum m/z 275 (M,
15%), 203 (28), 202 (39), 176 (12), 175 (100), 147 (62), 128
(45), 103 (65), 91 (20), 77 (41).
Attempted Alkylation of Diethyl Phenylpropanedioate with
N-(2-Bromoethyl)phthalimide
Hydrochloride Salt of Diethyl (2-Aminoethyl)(4-chlorophenyl)-
propanedioate (34)
The ester (32) was hydrogenated by the method of Leonard,15
but by using Adams’ catalyst. Recrystallization of the product
Diethyl phenylpropanedioate (1ꢀ0 ml, 4ꢀ64 mmol) was added
dropwise to a stirring suspension of sodium hydride (0ꢀ2 g of a

Potential GABA Receptor Antagonists. X
821
B
60% dispersion in mineral oil, 5ꢀ0 mmol) in dry tetrahydrofuran
(15 ml) at room temperature under nitrogen. After 0ꢀ5 h, a
solution of N-(2-bromoethyl)phthalimide (1ꢀ27 g, 5ꢀ0 mmol)
in tetrahydrofuran (4 ml) was added and the resultant mix-
ture stirred for 72 h. The reaction mixture was quenched
with saturated aqueous ammonium chloride solution (10 ml)
and extracted with ether (3ꢁ20 ml). The combined organic
extracts were washed with 10% aqueous sodium chloride solu-
tion (2ꢁ50 ml), dried, ꢀltered and evaporated to dryness. The
residue was subjected to radial chromatography on silica, with
a light petroleum/ethyl acetate gradient as eluent, to aꢂord
N-vinylphthalimide (38), isolated as a white solid (0ꢀ32 g,
40%), m.p. 83–86ꢁ (lit.28 84ꢁ). ꢀmax 2924, 2853, 1783, 1715,
ether (3ꢁ20 ml). The tetrahydrofuran and ethereal extracts
were combined, washed with saturated aqueous sodium chloride
solution (2ꢁ100 ml), dried, ꢀltered and concentrated to dryness.
Puriꢀcation of the crude residue by column chromatography
on silica gel, with 30% ethyl acetate in dichloromethane as
eluent, aꢂorded the ester (40) (3ꢀ81 g, 68%) as a colourless oil
(Found: M+ꢂ, 373ꢀ0831. C16H21ClNO5P requires 373ꢀ0845).
ꢀmax 2253, 1731, 1594, 1496, 1477, 1251, 1097, 1014, 979, 855,
830 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ22, t, J 7ꢀ1 Hz, 3H; 1ꢀ28, t, J 7ꢀ2 Hz,
3H; 1ꢀ35, t, J 7ꢀ2 Hz, 3H; 3ꢀ23, dd, J 16ꢀ5, JH–P 12ꢀ9 Hz, 1H;
3ꢀ36, dd, J 16ꢀ5, JH–P 8ꢀ1 Hz, 1H; 3ꢀ91–4ꢀ16, m, 4H; 4ꢀ38,
q, J 7ꢀ1 Hz, 2H; 7ꢀ37, d, J 8ꢀ9 Hz, 2H; 7ꢀ47, d, J 8ꢀ6 Hz,
2H. 13C n.m.r ꢁ 13ꢀ89; 16ꢀ21, apparent t, JC–P 5ꢀ3 Hz; 24ꢀ50;
55ꢀ45, d, JC–P 136ꢀ2 Hz; 62ꢀ99; 63ꢀ94, d, JC–P 7ꢀ2 Hz; 64ꢀ57,
d, JC–P 7ꢀ4 Hz; 116ꢀ35, d, JC–P 14ꢀ6 Hz; 128ꢀ98; 129ꢀ21, d,
JC–P 6ꢀ0 Hz; 131ꢀ98, d, JC–P 6ꢀ7 Hz; 134ꢀ71, d, JC–P 2ꢀ9 Hz;
167ꢀ79. Mass spectrum m/z 375/373 (M, 2/6%), 346/344
(7/20), 290/288 (2/7), 246/244 (4/14), 191 (100), 155 (37),
127/125 (10/5), 81 (16).
1635, 1302, 1217, 1165, 1027, 894 cmꢃ1
.
1H n.m.r. ꢁ 5ꢀ03,
d, J 9ꢀ8 Hz, 1H; 6ꢀ06, d, J 16ꢀ4 Hz, 1H; 6ꢀ06, dd, J 9ꢀ9,
16ꢀ5 Hz, 1H; 7ꢀ71–7ꢀ86, m, 4H. 13C n.m.r. ꢁ 104ꢀ43; 123ꢀ55;
123ꢀ77; 131ꢀ56; 134ꢀ45; 166ꢀ42.
3-Carbamoyl-2-(4-chlorophenyl)propanoic Acid (39)
A mixture of (32) (1ꢀ5 g, 4ꢀ85 mmol) and potassium hydrox-
ide (0ꢀ82 g, 14ꢀ64 mmol) in ethanol (35 ml) was heated at
reꢁux for 2ꢀ5 h. After the reaction mixture was evaporated
under vacuum the residue was redissolved in water (20 ml) and
washed with ether (3ꢁ20 ml). The aqueous phase was acidiꢀed
with 3 M hydrochloric acid and extracted with ether (3ꢁ25 ml).
The combined organic fractions were washed with saturated
aqueous sodium chloride solution (2ꢁ50 ml), dried, ꢀltered
and concentrated under reduced pressure to give a pale yel-
low residue. Puriꢀcation by recrystallization from ether/light
petroleum aꢂorded 2-(4-chlorophenyl)-3-cyanopropanoic acid
as a white solid (0ꢀ81 g, 80%), m.p. 94–96ꢁ (Found: C, 57ꢀ4;
H, 3ꢀ6; N, 7ꢀ0%; M+ꢂ, 209ꢀ0238. C10H8ClNO2 requires C,
57ꢀ3; H, 3ꢀ9; N, 6ꢀ7%; M+ꢂ; 209ꢀ0243). ꢀmax 3430, 2275,
Ethyl 3-Cyano-2-diethoxyphosphinyl-2-phenylpropanoate (41)
The ester (15) was alkylated as above with bromoacetoni-
trile. Puriꢀcation by column chromatography on silica gel, with
70% dichloromethane in ethyl acetate as eluent, furnished the
title compound (41) as a faint yellow oil (70%) (Found: M+ꢂ
,
339ꢀ1218. C16H22NO5P requires M+ꢂ, 339ꢀ1236). ꢀmax 2252,
1736, 1601, 1582, 1498, 1448, 1248, 1163, 1049, 757 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ18, t, J 7ꢀ2 Hz, 3H; 1ꢀ27, t, J 7ꢀ2 Hz, 3H;
1ꢀ36, t, J 7ꢀ2 Hz, 3H; 3ꢀ27, dd, J 16ꢀ5, JH–P 12ꢀ8 Hz, 1H;
3ꢀ36, dd, J 16ꢀ5, JH–P 8ꢀ1 Hz, 1H; 3ꢀ90–4ꢀ11, m, 4H; 4ꢀ39,
q, J 7ꢀ2 Hz, 2H; 7ꢀ36–7ꢀ51, m, 5H. 13C n.m.r. ꢁ 13ꢀ69; 15ꢀ98,
apparent t, JC–P 5ꢀ6 Hz; 24ꢀ41; 55ꢀ79, d, JC–P 136ꢀ9 Hz;
62ꢀ54; 63ꢀ54, d, JC–P 7ꢀ2 Hz; 64ꢀ25, d, JC–P 7ꢀ1 Hz; 116ꢀ37,
d, JC–P 13ꢀ4 Hz; 127ꢀ43, d, JC–P 5ꢀ5 Hz; 128ꢀ30; 128ꢀ51;
134ꢀ71, d, JC–P 6ꢀ5 Hz; 167ꢀ92. Mass spectrum m/z 339 (M,
20%), 310 (70), 266 (26), 254 (41), 210 (44), 157 (100), 155
(87), 128 (62), 103 (55), 77 (40), 65 (27).
1733, 1492, 1277, 1260, 1172, 1094, 857, 751 cmꢃ1 1H n.m.r.
.
ꢁ 2ꢀ80, dd, J 7ꢀ6, 16ꢀ9 Hz, 1H; 3ꢀ01, dd, J 7ꢀ4, 16ꢀ8 Hz, 1H;
3ꢀ95, apparent t, J 7ꢀ5 Hz, 1H; 7ꢀ26, d, J 8ꢀ4 Hz, 2H; 7ꢀ37,
d, J 8ꢀ4 Hz, 2H; 8ꢀ77, br s, 1H, OH (D2O exch.). 13C n.m.r. ꢁ
21ꢀ27; 46ꢀ87; 117ꢀ05; 129ꢀ09; 129ꢀ60; 133ꢀ46; 134ꢀ99; 175ꢀ76.
Mass spectrum m/z 211/209 (M, 15/46%), 166/164 (20/62),
140/138 (38/100), 77 (30).
Hydrochloride Salt of 3-Amino-1-(4-chlorophenyl)-
propylphosphonic Acid (42)
By using the general procedure of Roberts and Selby,16
a
A mixture of the ester (40) (2ꢀ1 g, 5ꢀ63 mmol), concentrated
hydrochloric acid (1ꢀ0 ml), platinum oxide (200 mg) and ethanol
(60 ml) was hydrogenated at 4 atm for 18 h at 65ꢁ. The mixture
was ꢀltered through Celite, and the ꢀltrate concentrated under
reduced pressure to give the hydrochloride salt of ethyl 4-
amino-2-(4-chlorophenyl)-2-diethoxyphosphinylbutanoate as a
pale yellow viscous oil (2ꢀ0 g, 94%), which was used in the
next step without any further puriꢀcation. ꢀmax 3396, 1732,
mixture of 2-(4-chlorophenyl)-3-cyanopropanoic acid (0ꢀ50 g,
2ꢀ39 mmol) and concentrated sulfuric acid (0ꢀ8 ml, 14ꢀ40 mmol)
was stirred at room temperature for 8 h before being poured
into water (15 ml). The precipitate was collected by vacuum
ꢀltration and recrystallized from ethanol/light petroleum to
aꢂord the title compound (39) as a white powder (0ꢀ35 g, 65%),
m.p. 173–175ꢁ (Found: C, 53ꢀ0; H, 4ꢀ6; N, 6ꢀ3%; M+ꢂ ꢂ NH3,
210ꢀ0099. C10H10ClNO3 requires C, 52ꢀ7; H, 4ꢀ4; N, 6ꢀ2%;
1637, 1494, 1369, 1240, 1160, 1097, 1021, 854 cmꢃ1 1H n.m.r.
.
C
10H7ClO3 requires m/z, 210ꢀ0084). ꢀmax 3450, 3195, 1701,
1653, 1577, 1490, 1287, 1184, 1014, 757 cmꢃ1
.
1H n.m.r. ꢁ
(CDCl3/triꢁuoroacetic acid) ꢁ 1ꢀ24, t, J 7ꢀ1 Hz, 3H; 1ꢀ28,
t, J 7ꢀ2 Hz, 3H; 1ꢀ34, t, J 7ꢀ2 Hz, 3H; 2ꢀ75–3ꢀ36, m, 4H;
3ꢀ94–4ꢀ39, m, 6H; 7ꢀ28–7ꢀ39, m, 4H. 13C n.m.r. (CDCl3/tri-
ꢁuoroacetic acid) ꢁ 13ꢀ46; 15ꢀ65, apparent t, JC–P 5ꢀ6 Hz,
2ꢁCH3; 31ꢀ79; 37ꢀ78, d, JC–P 7ꢀ4 Hz; 57ꢀ18, d, JC–P 141ꢀ9 Hz;
64ꢀ10; 65ꢀ76, d, JC–P 7ꢀ7 Hz; 66ꢀ04, d, JC–P 7ꢀ1 Hz; 128ꢀ79,
d, JC–P 5ꢀ6 Hz; 129ꢀ40; 131ꢀ51, d, JC–P 7ꢀ6 Hz; 135ꢀ33, d,
JC–P 3ꢀ0 Hz; 170ꢀ58.
2ꢀ81, dd, J 5ꢀ7, 15ꢀ9 Hz, 1H; 3ꢀ24, dd, J 9ꢀ6, 15ꢀ8 Hz, 1H;
4ꢀ22, dd, J 5ꢀ5, 9ꢀ6 Hz, 1H; 7ꢀ26, d, J 8ꢀ6 Hz, 2H; 7ꢀ37,
d, J 8ꢀ5 Hz, 2H; 8ꢀ11, br s, 3H, OH and NH2 (D2O exch.).
13C n.m.r. ꢁ 38ꢀ42; 46ꢀ84; 129ꢀ49; 130ꢀ10; 134ꢀ14; 135ꢀ47;
178ꢀ09; 179ꢀ75. Mass spectrum m/z 212/210 (M ꢂ NH3,
3/7%), 140/138 (31/100), 127/125 (7/25), 103 (29), 77 (18),
51 (41).
A mixture of the crude ester (0ꢀ35 g, 0ꢀ85 mmol) and con-
centrated hydrochloric acid (15 ml) was then heated at reꢁux
for 20 h. The reaction mixture was cooled and washed with
dichloromethane (3ꢁ15 ml). The aqueous phase was evaporated
to dryness. Puriꢀcation of the residue by recrystallization from
ethanol/ether aꢂorded the hydrochloride of the title compound
(42) as a white powder (0ꢀ21 g, 86%), m.p. 249–254ꢁ (dec.)
(Found: C, 37ꢀ7; H, 4ꢀ9; N, 4ꢀ9. C9H14Cl2NO3P requires C,
37ꢀ8; H, 4ꢀ9; N, 4ꢀ9%). ꢀmax 3641–2650(br), 1552, 1501, 1268,
Ethyl 2-(4-Chlorophenyl)-3-cyano-2-
diethoxyphosphinylpropanoate (40)
A solution of the acetate (14) (5ꢀ01 g, 15 mmol) in tetrahy-
drofuran (5 ml) was added dropwise to a stirring suspension
of sodium hydride (0ꢀ7 g of a 60% dispersion in mineral oil,
17ꢀ5 mmol) in dry tetrahydrofuran (80 ml) under nitrogen at
room temperature. When the evolution of hydrogen had ceased,
bromoacetonitrile (1ꢀ05 ml, 15 mmol) was added dropwise to
the reaction mixture and stirring was continued for 20 h. After
a solution of saturated aqueous ammonium chloride (20 ml)
was added, the aqueous layer was separated and extracted with
1146, 1094, 931, 893 cmꢃ1
4H; 3ꢀ86–3ꢀ97, m, 1H; 7ꢀ29, d, J 8ꢀ4 Hz, 2H; 7ꢀ38, d, J 8ꢀ6 Hz,
2H. 13C n.m.r. (D2O) ꢁ 31ꢀ88; 35ꢀ99; 46ꢀ54, d, JC–P 133ꢀ4 Hz;
.
1H n.m.r. (D2O) ꢁ 2ꢀ62–3ꢀ17, m,

822
R. H. Prager and K. Schafer
127ꢀ80, d, JC–P 3ꢀ2 Hz; 130ꢀ17, d, JC–P 5ꢀ7 Hz; 131ꢀ34, d,
JC–P 6ꢀ0 Hz; 134ꢀ64.
289 (M, 14%), 217 (39), 216 (68), 171 (84), 160 (41), 147 (34),
131 (44), 103 (65), 91 (12), 77 (21), 69 (100).
Hydrochloride Salt of 3-Amino-1-phenylpropylphosphonic
Acid (43)
Hydrochloride Salt of 5-Amino-2-(4-chlorophenyl)pentanoic
Acid (46)
Compound (41) (1ꢀ0 g, 2ꢀ95 mmol) was hydrogenated as
above to aꢂord the hydrochloride salt of ethyl 4-amino-2-
diethoxyphosphinyl-2-phenylbutanoate as a colourless viscous oil
(0ꢀ96 g, 86%), which was used in the next step without any fur-
ther puriꢀcation (Found: M+ꢂ ꢂ HCl, 343ꢀ1521. C16H26NO5P
requires m/z, 343ꢀ1548). ꢀmax 3410, 1727, 1623, 1447, 1393,
A mixture of the ester (44) (2ꢀ1 g, 6ꢀ5 mmol), concen-
trated hydrochloric acid (0ꢀ5 ml), platinum oxide (200 mg) and
ethanol (50 ml) was hydrogenated at 4 atm for 20 h at 65ꢁ. The
reaction mixture was cooled, ꢀltered through Celite and con-
centrated under reduced pressure to a give a pale yellow residue.
Recrystallization from ethanol/ether aꢂorded the hydrochloride
salt of diethyl (3-aminopropyl)(4-chlorophenyl)propanedioate
as white platelets (1ꢀ65 g, 70%), m.p. 108–110ꢁ (Found: C,
52ꢀ9; H, 6ꢀ8; N, 4ꢀ1%; M+ꢂ ꢂ HCl, 327ꢀ1211. C16H23Cl2NO4
requires C, 52ꢀ8; H, 6ꢀ4; N, 3ꢀ9%; C15H22ClNO4 requires m/z,
327ꢀ1237). ꢀmax 3350, 1733, 1613, 1524, 1480, 1240, 1040,
1325, 1044, 1023, 798 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ23, t, J 7ꢀ2 Hz,
3H; 1ꢀ27, t, J 7ꢀ1 Hz, 3H; 1ꢀ34, t, J 7ꢀ2 Hz, 3H; 2ꢀ72–3ꢀ33,
m, 4H; 3ꢀ89–4ꢀ31, m, 6H; 7ꢀ26–7ꢀ36, m, 5H; 8ꢀ32, br s, 3H,
NH3 (D2O exch.). 13C n.m.r. ꢁ 13ꢀ87; 16ꢀ12, d, JC–P 5ꢀ6 Hz;
+
16ꢀ29, d, JC–P 5ꢀ5 Hz; 31ꢀ35; 36ꢀ78, d, JC–P 8ꢀ9 Hz; 57ꢀ20,
d, JC–P 139ꢀ3 Hz; 62ꢀ54; 64ꢀ35, d, JC–P 7ꢀ5 Hz; 64ꢀ42, d,
JC–P 7ꢀ4 Hz; 127ꢀ94; 128ꢀ01; 128ꢀ61; 134ꢀ21, d, JC–P 7ꢀ6 Hz;
169ꢀ75. Mass spectrum m/z 343 (M ꢂ HCl, 2%), 298 (20), 254
(53), 187 (10), 103 (25), 84 (100), 69 (61).
862 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ26, t, J 7ꢀ1 Hz, 6H; 1ꢀ64–1ꢀ79, m,
2H; 2ꢀ32–2ꢀ44, m, 2H; 2ꢀ90–3ꢀ06, m, 2H; 4ꢀ11–4ꢀ27, m, 4H;
7ꢀ29, d, J 8ꢀ4 Hz, 2H; 7ꢀ36, d, J 8ꢀ4 Hz, 2H; 8ꢀ05, br s, 3H,
NH3 (D2O exch.). 13C n.m.r. ꢁ 13ꢀ98; 23ꢀ11; 32ꢀ56; 39ꢀ83;
+
The crude ester (0ꢀ4 g, 1ꢀ06 mmol) was reꢁuxed in con-
centrated hydrochloric acid (20 ml) to give the hydrochloride
salt of the amino acid (43) as a white powder (0ꢀ22 g, 83%),
after recrystallization from ethanol/ether, m.p. 237–240ꢁ (dec.)
(Found: C, 43ꢀ1; H, 6ꢀ3; N, 5ꢀ7. C9H15ClNO3P requires C,
42ꢀ9; H, 6ꢀ0; N, 5ꢀ6%). ꢀmax 3646–2643(br), 1540, 1499, 1271,
61ꢀ79; 62ꢀ09; 128ꢀ49; 129ꢀ55; 133ꢀ75; 135ꢀ19; 170ꢀ15. Mass
spectrum m/z 329/327 (M ꢂ HCl, 9/14%), 283/281 (8/16),
237/235 (6/13), 226/224 (30/68), 182/180 (11/28), 140/138
(20/31), 69 (100), 56 (35).
A solution of the above ester (1ꢀ1 g, 3ꢀ03 mmol) in 8 M
hydrochloric acid (30 ml) was heated at reꢁux for 16 h. The
reaction mixture was cooled and washed with dichloromethane
1135, 1087, 975, 927, 889 cmꢃ1
.
1H n.m.r. (D2O) ꢁ 2ꢀ60–3ꢀ19,
m, 4H; 3ꢀ89–3ꢀ97, m, 1H; 7ꢀ27–7ꢀ38, m, 5H. 13C n.m.r. (D2O)
ꢁ 30ꢀ84; 35ꢀ72; 45ꢀ99, d, JC–P 132ꢀ8 Hz; 127ꢀ64; 127ꢀ82;
128ꢀ87; 132ꢀ89, d, JC–P 6ꢀ6 Hz.
(3ꢁ30 ml).
The aqueous phase was evaporated to dry-
ness to give a pale yellow residue. Recrystallization from
ethanol/ether aꢂorded the hydrochloride salt of the title com-
pound (46) as white needles (0ꢀ64 g, 80%), m.p. 173–175ꢁ
(dec.) (Found: C, 50ꢀ1; H, 6ꢀ0; N, 5ꢀ4%; M+ꢂ ꢂ (HCl+H2O),
Diethyl (4-Chlorophenyl)(2-cyanoethyl)propanedioate (44)
This procedure is based on the method of Ansell and Hey.19
Diethyl (4-chlorophenyl)propanedioate (6ꢀ35 g, 23ꢀ5 mmol) was
added to a solution of 30% ethanolic potassium hydroxide (w/w,
0ꢀ5 ml) in anhydrous t-butyl alcohol (25 ml) at 40ꢁ under a
nitrogen atmosphere. After 0ꢀ5 h, acrylonitrile (1ꢀ60 ml,
23ꢀ5 mmol) was added and the reaction mixture was stirred at
room temperature for 48 h. The reaction mixture was quenched
with 2 M hydrochloric acid (5 ml), diluted with water (15 ml)
and extracted with ether (3ꢁ20 ml). The combined organic
extracts were washed with 10% aqueous sodium chloride solu-
tion (2ꢁ60 ml), dried, ꢀltered and concentrated under vacuum
to give a yellow residue. Puriꢀcation by distillation gave the
title compound (44) as a colourless oil (b.p. 145–147ꢁ/0ꢀ1 mm)
which solidiꢀed on cooling to aꢂord colourless crystals (6ꢀ21 g,
82%), m.p. 50–52ꢁ (Found: M+ꢂ, 323ꢀ0978. C16H1835ClNO4
requires M+ꢂ, 323ꢀ0924). ꢀmax 2249, 1730, 1494, 1448, 1368,
209ꢀ0613.
C
11H14ClNO2.HCl requires C, 50ꢀ0; H, 5ꢀ7; N,
5ꢀ3%; C11H12ClNO requires m/z, 209ꢀ0607). ꢀmax 3300–
2500(br), 1715, 1602, 1490, 1262, 1200, 1090, 1014 cmꢃ1
.
1H n.m.r. (D2O) ꢁ 1ꢀ73–1ꢀ89, m, 2H; 1ꢀ91–2ꢀ06, m, 1H;
2ꢀ21–2ꢀ31, m, 1H; 3ꢀ17, t, J 6ꢀ8 Hz, 2H; 3ꢀ88, apparent t,
J 7ꢀ7 Hz, 1H; 7ꢀ31, d, J 8ꢀ6 Hz, 2H; 7ꢀ39, d, J 8ꢀ6 Hz,
2H. 13C n.m.r. (D2O) ꢁ 24ꢀ70; 28ꢀ95; 39ꢀ25; 49ꢀ95; 128ꢀ98;
129ꢀ59; 132ꢀ94; 136ꢀ87; 177ꢀ50. Mass spectrum m/z 211/209
(M ꢂ (HCl+H2O), 33/100%), 155/153 (6/21), 140/138 (23/71),
127/125 (22/60), 77 (15).
Hydrochloride Salt of 5-Amino-2-phenylpentanoic Acid (47)
Compound (45) (2ꢀ1 g, 7ꢀ27 mmol) was hydrogenated as
above to aꢂord the hydrochloride salt of diethyl (3-aminopropyl)-
phenylpropanedioate as white platelets (1ꢀ56 g, 65%), after
recrystallization from ethanol/ether, m.p. 84–86ꢁ (Found: C,
58ꢀ1; H, 7ꢀ6; N, 4ꢀ3%; M+ꢂ ꢂ HCl, 293ꢀ1673. C16H24ClNO4
requires C, 58ꢀ3; H, 7ꢀ3; N, 4ꢀ25%; C16H23NO4 requires m/z,
293ꢀ1627). ꢀmax 3365, 1731, 1613, 1529, 1447, 1240, 1038,
1248, 1093, 1014, 859 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ26, t, J 7ꢀ1 Hz,
3H; 1ꢀ27, t, J 7ꢀ1 Hz, 3H; 2ꢀ34, t, J 8ꢀ2 Hz, 2H; 2ꢀ61, t,
J 8ꢀ1 Hz, 2H; 4ꢀ24–4ꢀ28, m, 4H; 7ꢀ27, d, J 8ꢀ6 Hz, 2H; 7ꢀ36,
d, J 8ꢀ6 Hz, 2H. 13C n.m.r. ꢁ 13ꢀ40; 13ꢀ94; 32ꢀ18; 61ꢀ27;
62ꢀ40; 118ꢀ89; 128ꢀ87; 129ꢀ15; 134ꢀ05; 134ꢀ30; 169ꢀ30. Mass
spectrum m/z 325/323 (M, 9/16%), 253/251 (11/39), 252/250
(19/37), 207/205 (17/47), 180/178 (16/89), 140/138 (28/57),
139/137 (33/29), 127/125 (5/24), 77 (13), 69 (100).
863 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ25, t, J 7ꢀ1 Hz, 6H; 1ꢀ65–1ꢀ76,
m, 2H; 2ꢀ30–2ꢀ41, m, 2H; 2ꢀ89–3ꢀ01, m, 2H; 4ꢀ12–4ꢀ28, m,
+
4H; 7ꢀ29–7ꢀ37, m, 5H; 8ꢀ01, br s, 3H, NH3 (D2O exch.).
13C n.m.r. ꢁ 13ꢀ70; 22ꢀ84; 32ꢀ16; 39ꢀ77; 61ꢀ71; 62ꢀ05; 127ꢀ42;
127ꢀ78; 128ꢀ05; 136ꢀ40; 170ꢀ37. Mass spectrum m/z 293
(M ꢂ HCl, 11%), 247 (23), 201 (18), 190 (100), 146 (27), 104
(43), 91 (19), 77 (13), 56 (30).
Diethyl (2-Cyanoethyl)phenylpropanedioate (45)
Diethyl phenylpropanedioate was alkylated as above. Puriꢀ-
cation of the crude residue by distillation gave the title compound
(45) as a colourless oil, b.p. 155ꢁ/1ꢀ0 mm (lit.16 186ꢁ/2ꢀ5 mm),
which solidiꢀed on cooling to give colourless crystals (13ꢀ11 g,
91%), m.p. 39–40ꢁ (lit.16 41ꢁ) (Found: M+ꢂ, 289ꢀ1346. Calc.
for C16H19NO4: M+ꢂ, 289ꢀ1314). ꢀmax 2248, 1736, 1602,
When the reaction was carried out in the absence of
concentrated hydrochloric acid, the reaction product was
shown by 1H n.m.r. spectroscopy to be ethyl 3-aza-2-oxo-1-
phenylcyclohexanecarboxylate (48). Puriꢀcation was achieved
by passing the crude product through a short plug of silica,
with a gradient of dichloromethane and ethyl acetate as eluent.
1497, 1448, 1391, 1252, 1096, 1027, 860 cmꢃ1
.
1H n.m.r. ꢁ
1ꢀ24, t, J 7ꢀ1 Hz, 3H; 1ꢀ25, t, J 7ꢀ1 Hz, 3H; 2ꢀ33, t, J 8ꢀ1 Hz,
2H; 2ꢀ62, t, J 8ꢀ2 Hz, 2H; 4ꢀ23–4ꢀ28, m, 4H; 7ꢀ28–7ꢀ36, m,
5H. 13C n.m.r. ꢁ 13ꢀ42; 13ꢀ94; 32ꢀ37; 61ꢀ83; 62ꢀ19; 119ꢀ20;
127ꢀ67; 128ꢀ59; 128ꢀ68; 135ꢀ59; 169ꢀ65. Mass spectrum m/z
ꢀmax 1734, 1706, 1447, 1397, 1367, 1259, 1095, 1025 cmꢃ1
.
1H n.m.r. ꢁ 1ꢀ26, t, J 7ꢀ2 Hz, 3H; 1ꢀ60–1ꢀ79, m, 2H; 2ꢀ05,
br s, 1H, NH (D2O exch.); 2ꢀ29–2ꢀ38, m, 1H; 2ꢀ64–2ꢀ73, m,
1H; 3ꢀ30–3ꢀ39, m, 2H; 4ꢀ26, q, J 7ꢀ2 Hz, 2H; 7ꢀ30–7ꢀ39, m,

Potential GABA Receptor Antagonists. X
823
B
3
4
5H. 13C n.m.r. ꢁ 14ꢀ06; 18ꢀ46; 32ꢀ64; 42ꢀ25; 60ꢀ51; 61ꢀ91;
127ꢀ29; 127ꢀ94; 128ꢀ29; 138ꢀ87; 170ꢀ35; 172ꢀ72.
Nobuyuki, H., Yasuhiro, N., Youichi, H., and Yoshiaki, G.,
Eur. J. Pharmacol., 1990, 179, 17.
Ong, J., Kerr, D. I. B., Abbenate, J., and Prager, R. H.,
Eur. J. Pharmacol., 1991, 205, 319.
Prager, R. H., Schafer, K., Hamon, D. P. G., and Massy-
Westropp, R. A., Tetrahedron, 1995, 51, 11465.
Heath, R. H., and Piggott, H. A., J. Chem. Soc., 1947,
1481.
Kerr, D. I. B., Ong, J., Abbenate, J., and Prager, R. H.,
Eur. J. Pharmacol., 1993, 236, 239.
Abbenante, G., Hughes, R., and Prager, R. H., Aust. J.
Chem., 1994, 47, 1441.
Bauer, I., and Exner, O., Angew. Chem., Int. Ed. Engl.,
1974, 13, 376.
Nagarajan, K., Rajappa, S., Rajagopalan, P., and Tal-
walkar, P. K., Indian J. Chem., Sect. B., 1991, 30, 222,
and references therein.
Kehl, H., Arch. Int. Pharmacodyn. Ther., 1984, 270, 232
(Chem. Abstr., 1984, 101, 163542W).
Yamasaki, K., and Goto, Y., Jpn. J. Pharmacol., 1990,
54, 7.
Yamasaki, K., Goto, Y., Hara, N., and Hara, Y., Jpn. J.
Pharmacol., 1991, 55, 11.
Wall, M. G., and Baker, J. K., J. Med. Chem., 1989, 32,
1340.
Leonard, F., U.S. Pat. 3,125,583 (1964) (Chem. Abstr.,
1964, 60, 13193a).
Roberts, J. C., and Selby, K., J. Chem. Soc., 1951, 2335.
Chiefari, J., Galanopoulos, S., Janowski, W. K., Kerr, D. I. B.,
and Prager, R., Aust. J. Chem., 1987, 40, 1511.
Kerr, D. I. B., Ong, J., Prager, R. H., Gynther, B. D., and
Curtis, D. R., Brain Res., 1987, 405, 150.
Ansell, M. F., and Hay, D. H., J. Chem. Soc., 1950, 1683.
Diethyl (3-aminopropyl)phenylpropanedioate (1ꢀ2 g, 3ꢀ65
mmol) was treated with 8 M hydrochloric acid (30 ml) to give
the hydrochloride salt of the amino acid (47) as a white
solid (0ꢀ65 g, 78%), after recrystallization from ethanol/ether,
m.p. 127–129ꢁ (dec.) (Found: C, 57ꢀ3; H, 6ꢀ9; N, 5ꢀ7%;
5
6
M
+ꢂ ꢂ (HCl+H2O), 175ꢀ1008. C11H16ClNO2 requires C, 57ꢀ5;
7
H, 7ꢀ0; N, 6ꢀ1%; C11H13NO requires m/z, 175ꢀ0997). ꢀmax
3320–2560(br), 1727, 1619, 1346, 1263, 1179, 1018, 876 cmꢃ1
.
8
1H n.m.r. (D2O) ꢁ 1ꢀ77–1ꢀ95, m, 2H; 2ꢀ05–2ꢀ14, m, 1H;
2ꢀ26–2ꢀ38, m, 1H; 3ꢀ20, t, J 6ꢀ8 Hz, 2H; 3ꢀ94, apparent t,
J 7ꢀ7 Hz, 1H; 7ꢀ28–7ꢀ35, m, 5H. 13C n.m.r. (D2O) ꢁ 24ꢀ82;
29ꢀ07; 39ꢀ32; 50ꢀ62; 127ꢀ97; 128ꢀ10; 129ꢀ23; 132ꢀ38; 177ꢀ95.
Mass spectrum m/z 175 (M ꢂ (HCl+H2O), 75%), 119 (68),
104 (91), 91 (100), 77 (27), 56 (32).
9
10
11
12
13
14
15
4-Carbamoyl-2-(4-chlorophenyl)butanoic Acid (49)
The ester (44) was hydrolysed as above. Recrystallization
from ethanol/ether aꢂorded 2-(4-chlorophenyl)-4-cyanobutanoic
acid as a white solid (2ꢀ01 g, 90%), m.p. 65–66ꢁ (Found: C,
59ꢀ3; H, 4ꢀ6; N, 6ꢀ6%; M+ꢂ, 223ꢀ0381. C11H10ClNO2 requires
C, 59ꢀ1; H, 4ꢀ5; N, 6ꢀ3%; M+ꢂ, 223ꢀ0400). ꢀmax 3482, 2253,
1727, 1492, 1415, 1231, 1092, 1044, 1015, 938, 876 cmꢃ1
.
1H n.m.r. ꢁ 2ꢀ05–2ꢀ45, m, 4H; 3ꢀ72, apparent t, J 7ꢀ8 Hz, 1H;
7ꢀ26, d, J 8ꢀ5 Hz, 2H; 7ꢀ35, d, J 8ꢀ5 Hz, 2H; 9ꢀ95, br s, 1H,
OH (D2O exch.). 13C n.m.r. ꢁ 15ꢀ09; 28ꢀ11; 49ꢀ09; 118ꢀ42;
129ꢀ32; 129ꢀ36; 134ꢀ30; 134ꢀ59; 177ꢀ83. Mass spectrum m/z
225/223 (M, 10/41%), 180/178 (30/100), 140/138 (33/80),
127/125 (5/13), 91 (13), 77 (20).
16
17
18
A
mixture of 2-(4-chlorophenyl)-4-cyanobutanoic acid
(0ꢀ80 g, 3ꢀ59 mmol) and concentrated sulfuric acid (2ꢀ11 g,
21ꢀ54 mmol) was stirred at room temperature for 8 h. Workup
followed by recrystallization from ether/light petroleum fur-
nished the title compound (49) as a white powder (0ꢀ70 g,
81%), m.p. 159–161ꢁ (Found: C, 54ꢀ9; H, 5ꢀ2; N, 5ꢀ9%.
19
20
Kerr, D. I. B., Ong, J., and Prager, R. H., in ‘GABA
B
Receptors in Mammalian Function’ (Eds N. G. Bowery,
H. Bittiger and H.-R. Olpe), Ch. 2, pp. 29–45 (John Wiley:
Chichester 1990).
Perrin, D. D., Armarego, W. L. F., and Perrin, D. R.,
‘Puriꢀcation of Laboratory Chemicals’ 2nd Edn (Pergamon
Press: Oxford 1980).
Zvilichovsky, G., and Fotadar, U., Org. Prep. Proced. Int.,
1974, 6, 5.
Pucher, G. W., and Johnson, T. B., J. Am. Chem. Soc.,
1922, 44, 817; Winstead, M. B., and Heine, H. W., J. Am.
Chem. Soc., 1955, 77, 1913.
C
11H12ClNO3 requires C, 54ꢀ7; H, 5ꢀ0; N, 5ꢀ8%). ꢀmax 3420,
21
1701, 1655, 1594, 1492, 1320, 1257, 1200, 1094, 1014, 820 cmꢃ1
.
1H n.m.r. (CDCl3/triꢁuoroacetic acid) ꢁ 2ꢀ12–2ꢀ46, m, 4H;
3ꢀ63–3ꢀ74, m, 1H; 7ꢀ27, d, J 8ꢀ5 Hz, 2H; 7ꢀ38, d, J 8ꢀ5 Hz,
2H. 13C n.m.r. (CDCl3/triꢁuoroacetic acid) ꢁ 27ꢀ80; 32ꢀ34;
49ꢀ80; 129ꢀ38; 129ꢀ61; 134ꢀ32; 134ꢀ90; 179ꢀ91; 180ꢀ76. Mass
spectrum m/z 243/241 (M, 6/52%), 140/138 (40/100), 127/125
(2/8), 77 (20).
22
23
24
25
26
27
28
Cox, R. J., and O’Hagan, D., J. Chem. Soc., Perkin Trans. 1,
1991, 2537.
Robert, A., Jaguelin, S., and Guinamant, J. L., Tetrahedron,
1986, 42, 2275.
Berry, J. P., Isbell, A. F., and Hunt, G. E., J. Org. Chem.,
1972, 37, 4396.
Barycki, J., Mastalerz, P., and Soroka, M., Tetrahedron
Lett., 1970, 3147.
Acknowledgments
The authors are grateful to the Australian Research
Council for ꢀnancial support, and to Drs D. I. B. Kerr
and J. Ong for the biological testing results.
References
1
Abbenante, G., Hughes, R., and Prager, R. H., Aust. J.
Chem., 1997, 50, 523.
Hughes, R., and Prager, R. H., Aust. J. Chem., 1997, 50,
19.
Furukaqa, J., Onishi, A., and Tsuruta, T., J. Org. Chem.,
1958, 23, 672.
2